Skip to main content
SpringerLink
Log in

Crosstalk Between Prostate Cancer Stem Cells and Immune Cells: Implications for Tumor Progression and Resistance to Immunotherapy

  • Chapter
  • First Online:
Cancer Stem Cell Resistance to Targeted Therapy

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 19))

Abstract

Prostate cancer is a prototypical example of cancer as a disease of stem cells. Indeed, both normal and malignant prostate epithelia contain an androgen-independent, self-renewing stem cell population that survives in androgen deprivation conditions and can regenerate the complexity and heterogeneity of the tissue when androgens are either replaced, as for normal murine prostate in androgen-cycling experiments, or not replaced as it occurs in castrated prostate cancer patients. Thus, identification of prostate cancer stem-like cells (PCSC) and comprehension of the mechanisms regulating their function and interactions with the tumor microenvironment are of paramount importance in designing effective therapeutic strategies for prostate cancer patients. Here, we will focus on known and potential interactions between PCSCs and the immune system that may either block or favor cancer progression, depending on PCSC-intrinsic and PCSC-extrinsic mechanisms. We will also underline the clinical and biological needs to be addressed in the near future to increase efficacy of prostate cancer immunotherapies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AR:

Androgen receptor

CAR:

Chimeric antigen receptor

CK:

Cytokeratin

CSC:

Cancer stem cell

CTC:

Circulating tumor cell

CTLA-4:

Cytotoxic T-lymphocyte antigen 4

DC:

Dendritic cell

DHT:

Dihydrotestosterone

DTC:

Disseminated tumor cell

EMT:

Epithelial-mesenchymal transition

ESC:

Embryonic stem cell

GITR:

Glucocorticoid-induced tumor necrosis factor receptor family-related gene

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

HGPIN:

High-grade prostatic intraepithelial neoplasia

HLA:

Human leukocyte antigen

IDO:

Indoleamine 2,3-dioxygenase

IFN-γ:

Interferon-γ

IL-10:

Interleukin-10

IL-6:

Interleukin-6

iNKT:

Invariant natural killer T cells

iNOS:

Immunosuppressive NO synthase-2

LN:

Lymph node

M-CSF:

Macrophage colony-stimulating factor

MDSC:

Myeloid-derived suppressor cell

MHC:

Major histocompatibility complex

MØ:

Macrophage

mPIN:

Mouse prostatic intraepithelial neoplasia

MSC:

Mesenchymal stem cells

NE:

Neuroendocrine

NO:

Nitric oxide

PAP:

Prostate acid phosphatase

PCSC:

Prostate cancer stem-like cell

PROM1:

Prominin-1

PSA:

Prostate-specific antigen

PSCA:

Prostate stem cell antigen

PSMA:

Prostate-specific membrane antigen

STAT:

Transducers and activators of transcription

STEAP:

Six-transmembrane epithelial antigen of the prostate

Syn:

Synaptophysin

TAM:

Tumor-associated macrophage

TCR:

T cell receptor

TGF-β:

Transforming growth factor β

Th17:

T helper 17

TNC:

Tenascin-C

TNE-SCs:

PCSCs from mPIN lesions

TNF:

Tumor necrosis factor

TPIN-SCs:

PCSCs from NE tumors

TRAMP:

Transgenic adenocarcinoma of the mouse prostate

Treg:

Regulatory T cell

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.

    Article  PubMed  Google Scholar 

  2. Bell KJ, Del Mar C, Wright G, Dickinson J, Glasziou P. Prevalence of incidental prostate cancer: a systematic review of autopsy studies. Int J Cancer. 2015;137(7):1749–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Makarov DV, Humphreys EB, Mangold LA, Carducci MA, Partin AW, Eisenberger MA, Walsh PC, Trock BJ. The natural history of men treated with deferred androgen deprivation therapy in whom metastatic prostate cancer developed following radical prostatectomy. J Urol. 2008;179(1):156–61; discussion 161–152.

    Article  PubMed  Google Scholar 

  4. Ferrari AC, Stone NN, Kurek R, Mulligan E, McGregor R, Stock R, Unger P, Tunn U, Kaisary A, Droller M, Hall S, Renneberg H, Livak KJ, Gallagher RE, Mandeli J. Molecular load of pathologically occult metastases in pelvic lymph nodes is an independent prognostic marker of biochemical failure after localized prostate cancer treatment. J Clin Oncol. 2006;24(19):3081–8.

    Article  CAS  PubMed  Google Scholar 

  5. Javadar H. Prostate cancer. In: Juweid ME, Hoekstra OS, editors. Methods in molecular biology. New Jersey: Humana Press; 2011. p. 265–90.

    Google Scholar 

  6. Dickinson SI. Premalignant and malignant prostate lesions: pathologic review. Cancer Control. 2010;17(4):214–22.

    Article  PubMed  Google Scholar 

  7. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7(4):256–69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Gittes RF. Carcinoma of the prostate. N Engl J Med. 1991;324(4):236–45.

    Article  CAS  PubMed  Google Scholar 

  9. Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PS. Autonomic nerve development contributes to prostate cancer progression. Science. 2013;341(6142):1236361.

    Article  PubMed  Google Scholar 

  10. Bostwick DG, Dousa MK, Crawford BG, Wollan PC. Neuroendocrine differentiation in prostatic intraepithelial neoplasia and adenocarcinoma. Am J Surg Pathol. 1994;18(12):1240–6.

    Article  CAS  PubMed  Google Scholar 

  11. Komiya A, Suzuki H, Imamoto T, Kamiya N, Nihei N, Naya Y, Ichikawa T, Fuse H. Neuroendocrine differentiation in the progression of prostate cancer. Int J Urol. 2009;16(1):37–44.

    Article  PubMed  Google Scholar 

  12. English HF, Santen RJ, Isaacs JT. Response of glandular versus basal rat ventral prostatic epithelial cells to androgen withdrawal and replacement. Prostate. 1987;11(3):229–42.

    Article  CAS  PubMed  Google Scholar 

  13. Isaacs JT. Control of cell proliferation and cell death in the normal and neoplastic prostate: a stem cell model In: CH Rogers, Coffey DS, G Cunha, JT Grayhack, F Jr Hinman, R Horton editor. Benign prostatic hyperplasia. 87-2881. Washington D.C. US Department of Health and Human Services: NIH Publication; 1985. p. 85–94.

    Google Scholar 

  14. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65(23):10946–51.

    Article  CAS  PubMed  Google Scholar 

  15. Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG. Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+alpha2beta1+ cell population is enriched in tumor-initiating cells. Cancer Res. 2007;67(14):6796–805.

    Article  CAS  PubMed  Google Scholar 

  16. Miki J, Furusato B, Li H, Gu Y, Takahashi H, Egawa S, Sesterhenn IA, McLeod DG, Srivastava S, Rhim JS. Identification of putative stem cell markers, CD133 and CXCR4, in hTERT-immortalized primary nonmalignant and malignant tumor-derived human prostate epithelial cell lines and in prostate cancer specimens. Cancer Res. 2007;67(7):3153–61.

    Article  CAS  PubMed  Google Scholar 

  17. Vander Griend DJ, Karthaus WL, Dalrymple S, Meeker A, DeMarzo AM, Isaacs JT. The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. Cancer Res. 2008;68(23):9703–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hurt EM, Kawasaki BT, Klarmann GJ, Thomas SB, Farrar WL. CD44+ CD24(-) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Brit J Cancer. 2008;98(4):756–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Guzman-Ramirez N, Voller M, Wetterwald A, Germann M, Cross NA, Rentsch CA, Schalken J, Thalmann GN, Cecchini MG. In vitro propagation and characterization of neoplastic stem/progenitor-like cells from human prostate cancer tissue. Prostate. 2009;69(15):1683–93.

    Article  CAS  PubMed  Google Scholar 

  20. Goldstein AS, Huang J, Guo C, Garraway IP, Witte ON. Identification of a cell of origin for human prostate cancer. Science. 2010;329(5991):568–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Eaton CL, Colombel M, van der Pluijm G, Cecchini M, Wetterwald A, Lippitt J, Rehman I, Hamdy F, Thalman G. Evaluation of the frequency of putative prostate cancer stem cells in primary and metastatic prostate cancer. Prostate. 2010;70(8):875–82.

    PubMed  Google Scholar 

  22. Bae KM, Su Z, Frye C, McClellan S, Allan RW, Andrejewski JT, Kelley V, Jorgensen M, Steindler DA, Vieweg J, Siemann DW. Expression of pluripotent stem cell reprogramming factors by prostate tumor initiating cells. J Urol. 2010;183(5):2045–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Lippitt JM, Guzman-Ramirez N, Hamdy FC, Eaton CL, Thalmann GN, Cecchini MG, Pelger RC, van der Pluijm G. High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res. 2010;70(12):5163–73.

    Article  PubMed  CAS  Google Scholar 

  24. Rajasekhar VK, Studer L, Gerald W, Socci ND, Scher HI. Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-kappaB signalling. Nat Commun. 2011;2:162.

    Article  PubMed  CAS  Google Scholar 

  25. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, Patrawala L, Yan H, Jeter C, Honorio S, Wiggins JF, Bader AG, Fagin R, Brown D, Tang DG. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011;17(2):211–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Taylor RA, Toivanen R, Frydenberg M, Pedersen J, Harewood L, Australian Prostate Cancer B, Collins AT, Maitland NJ, Risbridger GP. Human epithelial basal cells are cells of origin of prostate cancer, independent of CD133 status. Stem Cells. 2012;30(6):1087–96.

    Article  CAS  PubMed  Google Scholar 

  27. Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, Castillo-Martin M, Quinn SA, Rodriguez-Barrueco R, Bonal DM, Charytonowicz E, Gladoun N, de la Iglesia-Vicente J, Petrylak DP, Benson MC, Silva JM, Cordon-Cardo C. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell. 2012;22(3):373–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Germann M, Wetterwald A, Guzman-Ramirez N, van der Pluijm G, Culig Z, Cecchini MG, Williams ED, Thalmann GN. Stem-like cells with luminal progenitor phenotype survive castration in human prostate cancer. Stem Cells. 2012;30(6):1076–86.

    Article  CAS  PubMed  Google Scholar 

  29. Stoyanova T, Cooper AR, Drake JM, Liu X, Armstrong AJ, Pienta KJ, Zhang H, Kohn DB, Huang J, Witte ON, Goldstein AS. Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells. Proc Natl Acad Sci U S A. 2013;110(50):20111–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gao D, Vela I, Sboner A, Iaquinta PJ, Karthaus WR, Gopalan A, Dowling C, Wanjala JN, Undvall EA, Arora VK, Wongvipat J, Kossai M, Ramazanoglu S, Barboza LP, Di W, Cao Z, Zhang QF, Sirota I, Ran L, MacDonald TY, Beltran H, Mosquera JM, Touijer KA, Scardino PT, Laudone VP, Curtis KR, Rathkopf DE, Morris MJ, Danila DC, Slovin SF, Solomon SB, Eastham JA, Chi P, Carver B, Rubin MA, Scher HI, Clevers H, Sawyers CL, Chen Y. Organoid cultures derived from patients with advanced prostate cancer. Cell. 2014;159(1):176–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Karthaus WR, Iaquinta PJ, Drost J, Gracanin A, van Boxtel R, Wongvipat J, Dowling CM, Gao D, Begthel H, Sachs N, Vries RG, Cuppen E, Chen Y, Sawyers CL, Clevers HC. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell. 2014;159(1):163–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rane JK, Scaravilli M, Ylipaa A, Pellacani D, Mann VM, Simms MS, Nykter M, Collins AT, Visakorpi T, Maitland NJ. MicroRNA expression profile of primary prostate cancer stem cells as a source of biomarkers and therapeutic targets. Eur Urol. 2015;67(1):7–10.

    Article  CAS  PubMed  Google Scholar 

  33. Smith BA, Sokolov A, Uzunangelov V, Baertsch R, Newton Y, Graim K, Mathis C, Cheng D, Stuart JM, Witte ON. A basal stem cell signature identifies aggressive prostate cancer phenotypes. Proc Natl Acad Sci U S A. 2015;112(47):E6544–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu X, Chen X, Rycaj K, Chao HP, Deng Q, Jeter C, Liu C, Honorio S, Li H, Davis T, Suraneni M, Laffin B, Qin J, Li Q, Yang T, Whitney P, Shen J, Huang J, Tang DG. Systematic dissection of phenotypic, functional, and tumorigenic heterogeneity of human prostate cancer cells. Oncotarget. 2015;6(27):23959–86.

    PubMed  PubMed Central  Google Scholar 

  35. Tang KD, Holzapfel BM, Liu J, Lee TK, Ma S, Jovanovic L, An J, Russell PJ, Clements JA, Hutmacher DW, Ling MT. Tie-2 regulates the stemness and metastatic properties of prostate cancer cells. Oncotarget. 2016;7(3):2572–84.

    PubMed  Google Scholar 

  36. Bernardo MM, Kaplun A, Dzinic SH, Li X, Irish J, Mujagic A, Jakupovic B, Back JB, Van Buren E, Han X, Dean I, Chen YQ, Heath E, Sakr W, Sheng S. Maspin expression in prostate tumor cells averts stemness and stratifies drug sensitivity. Cancer Res. 2015;75(18):3970–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang D, Park D, Zhong Y, Lu Y, Rycaj K, Gong S, Chen X, Liu X, Chao HP, Whitney P, Calhoun-Davis T, Takata Y, Shen J, Iyer VR, Tang DG. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer. Nat Commun. 2016;7:10798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen X, Li Q, Liu X, Liu C, Liu R, Rycaj K, Zhang D, Liu B, Jeter C, Calhoun-Davis T, Lin K, Lu Y, Chao HP, Shen J, Tang DG. Defining a population of stem-like human prostate cancer cells that can generate and propagate castration-resistant prostate cancer. Clin Cancer Res. 2016;22(17):4505–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Huss WJ, Gray DR, Greenberg NM, Mohler JL, Smith GJ. Breast cancer resistance protein-mediated efflux of androgen in putative benign and malignant prostate stem cells. Cancer Res. 2005;65(15):6640–50.

    Article  CAS  PubMed  Google Scholar 

  40. Wang S, Garcia AJ, Wu M, Lawson DA, Witte ON, Wu H. Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation. Proc Natl Acad Sci U S A. 2006;103(5):1480–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhou Z, Flesken-Nikitin A, Nikitin AY. Prostate cancer associated with p53 and Rb deficiency arises from the stem/progenitor cell-enriched proximal region of prostatic ducts. Cancer Res. 2007;67(12):5683–90.

    Article  CAS  PubMed  Google Scholar 

  42. Mulholland DJ, Xin L, Morim A, Lawson D, Witte O, Wu H. Lin-Sca-1+CD49fhigh stem/progenitors are tumor-initiating cells in the Pten-null prostate cancer model. Cancer Res. 2009;69(22):8555–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang X, Kruithof-de Julio M, Economides KD, Walker D, Yu H, Halili MV, Hu YP, Price SM, Abate-Shen C, Shen MM. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature. 2009;461(7263):495–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lukacs RU, Memarzadeh S, Wu H, Witte ON. Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell. 2010;7(6):682–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Abou-Kheir WG, Hynes PG, Martin PL, Pierce R, Kelly K. Characterizing the contribution of stem/progenitor cells to tumorigenesis in the Pten-/-TP53-/- prostate cancer model. Stem Cells. 2010;28(12):2129–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jiao J, Hindoyan A, Wang S, Tran LM, Goldstein AS, Lawson D, Chen D, Li Y, Guo C, Zhang B, Fazli L, Gleave M, Witte ON, Garraway IP, Wu H. Identification of CD166 as a surface marker for enriching prostate stem/progenitor and cancer initiating cells. PLoS One. 2012;7(8):e42564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kwon OJ, Zhang L, Ittmann MM, Xin L. Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin. Proc Natl Acad Sci U S A. 2014;111(5):E592–600.

    Article  CAS  PubMed  Google Scholar 

  48. Yoshioka T, Otero J, Chen Y, Kim YM, Koutcher JA, Satagopan J, Reuter V, Carver B, de Stanchina E, Enomoto K, Greenberg NM, Scardino PT, Scher HI, Sawyers CL, Giancotti FG. beta4 Integrin signaling induces expansion of prostate tumor progenitors. J Clin Invest. 2013;123(2):682–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Wang ZA, Mitrofanova A, Bergren SK, Abate-Shen C, Cardiff RD, Califano A, Shen MM. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat Cell Biol. 2013;15(3):274–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cheng CY, Hwang CI, Corney DC, Flesken-Nikitin A, Jiang L, Oner GM, Munroe RJ, Schimenti JC, Hermeking H, Nikitin AY. miR-34 cooperates with p53 in suppression of prostate cancer by joint regulation of stem cell compartment. Cell Rep. 2014;6(6):1000–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mazzoleni S, Jachetti E, Morosini S, Grioni M, Piras IS, Pala M, Bulfone A, Freschi M, Bellone M, Galli R. Gene signatures distinguish stage-specific prostate cancer stem cells isolated from transgenic adenocarcinoma of the mouse prostate lesions and predict the malignancy of human tumors. Stem Cells Transl Med. 2013;2(9):678–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chua CW, Shibata M, Lei M, Toivanen R, Barlow LJ, Bergren SK, Badani KK, McKiernan JM, Benson MC, Hibshoosh H, Shen MM. Single luminal epithelial progenitors can generate prostate organoids in culture. Nat Cell Biol. 2014;16(10):951–61, 951–954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang ZA, Toivanen R, Bergren SK, Chambon P, Shen MM. Luminal cells are favored as the cell of origin for prostate cancer. Cell Rep. 2014;8(5):1339–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Agarwal S, Hynes PG, Tillman HS, Lake R, Abou-Kheir WG, Fang L, Casey OM, Ameri AH, Martin PL, Yin JJ, Iaquinta PJ, Karthaus WR, Clevers HC, Sawyers CL, Kelly K. Identification of different classes of luminal progenitor cells within prostate tumors. Cell Rep. 2015;13(10):2147–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lawson DA, Witte ON. Stem cells in prostate cancer initiation and progression. J Clin Invest. 2007;117(8):2044–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Maitland NJ, Collins AT. Prostate cancer stem cells: a new target for therapy. J Clin Oncol. 2008;26(17):2862–70.

    Article  PubMed  Google Scholar 

  57. Wang ZA, Shen MM. Revisiting the concept of cancer stem cells in prostate cancer. Oncogene. 2011;30(11):1261–71.

    Article  PubMed  CAS  Google Scholar 

  58. Visvader JE. Cells of origin in cancer. Nature. 2011;469(7330):314–22.

    Article  CAS  PubMed  Google Scholar 

  59. Goldstein AS, Witte ON. A plethora of progenitors in the post-natal prostate. EMBO Rep. 2012;13(12):1036–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rybak AP, Bristow RG, Kapoor A. Prostate cancer stem cells: deciphering the origins and pathways involved in prostate tumorigenesis and aggression. Oncotarget. 2015;6(4):1900–19.

    Article  PubMed  Google Scholar 

  61. Clarke MF, Fuller M. Stem cells and cancer: two faces of eve. Cell. 2006;124(6):1111–5.

    Article  CAS  PubMed  Google Scholar 

  62. Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 2010;24(18):1967–2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O, Ellisman MH, Verma IM. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science. 2012;338(6110):1080–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM. Cancer stem cells–perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res. 2006;66(19):9339–44.

    Article  CAS  PubMed  Google Scholar 

  65. Adams JM, Strasser A. Is tumor growth sustained by rare cancer stem cells or dominant clones? Cancer Res. 2008;68(11):4018–21.

    Article  CAS  PubMed  Google Scholar 

  66. Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 2009;138(5):822–9.

    Article  CAS  PubMed  Google Scholar 

  67. Frank NY, Schatton T, Frank MH. The therapeutic promise of the cancer stem cell concept. J Clin Invest. 2010;120(1):41–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Greaves M, Maley CC. Clonal evolution in cancer. Nature. 2012;481(7381):306–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10(6):717–28.

    Article  CAS  PubMed  Google Scholar 

  70. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8(10):755–68.

    Article  CAS  PubMed  Google Scholar 

  71. Collins AT, Habib FK, Maitland NJ, Neal DE. Identification and isolation of human prostate epithelial stem cells based on alpha(2)beta(1)-integrin expression. J Cell Sci. 2001;114(Pt 21):3865–72.

    CAS  PubMed  Google Scholar 

  72. Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci. 2004;117(Pt 16):3539–45.

    Article  CAS  PubMed  Google Scholar 

  73. Reynolds BA, Weiss S. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol. 1996;175(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  74. Greenberg NM, DeMayo F, Finegold MJ, Medina D, Tilley WD, Aspinall JO, Cunha GR, Donjacour AA, Matusik RJ, Rosen JM. Prostate cancer in a transgenic mouse. Proc Natl Acad Sci U S A. 1995;92(8):3439–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Evangelou AI, Winter SF, Huss WJ, Bok RA, Greenberg NM. Steroid hormones, polypeptide growth factors, hormone refractory prostate cancer, and the neuroendocrine phenotype. J Cell Biochem. 2004;91(4):671–83.

    Article  CAS  PubMed  Google Scholar 

  76. Hansel DE, Nakayama M, Luo J, Abukhdeir AM, Park BH, Bieberich CJ, Hicks JL, Eisenberger M, Nelson WG, Mostwin JL, De Marzo AM. Shared TP53 gene mutation in morphologically and phenotypically distinct concurrent primary small cell neuroendocrine carcinoma and adenocarcinoma of the prostate. Prostate. 2009;69(6):603–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lee JK, Phillips JW, Smith BA, Park JW, Stoyanova T, McCaffrey EF, Baertsch R, Sokolov A, Meyerowitz JG, Mathis C, Cheng D, Stuart JM, Shokat KM, Gustafson WC, Huang J, Witte ON. N-Myc drives neuroendocrine prostate cancer initiated from human prostate epithelial cells. Cancer Cell. 2016;29(4):536–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, Wang Y, Sheikh KL, Terry S, Tagawa ST, Dhir R, Nelson JB, de la Taille A, Allory Y, Gerstein MB, Perner S, Pienta KJ, Chinnaiyan AM, Collins CC, Gleave ME, Demichelis F, Nanus DM, Rubin MA. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 2011;1(6):487–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, Marotz C, Giannopoulou E, Chakravarthi BV, Varambally S, Tomlins SA, Nanus DM, Tagawa ST, Van Allen EM, Elemento O, Sboner A, Garraway LA, Rubin MA, Demichelis F. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22(3):298–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JM, Papaemmanuil E, Brewer DS, Kallio HM, Hognas G, Annala M, Kivinummi K, Goody V, Latimer C, O’Meara S, Dawson KJ, Isaacs W, Emmert-Buck MR, Nykter M, Foster C, Kote-Jarai Z, Easton D, Whitaker HC, Neal DE, Cooper CS, Eeles RA, Visakorpi T, Campbell PJ, McDermott U, Wedge DC, Bova GS. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520(7547):353–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chiaverotti T, Couto SS, Donjacour A, Mao JH, Nagase H, Cardiff RD, Cunha GR, Balmain A. Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. Am J Pathol. 2008;172(1):236–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Blanpain C, Simons BD. Unravelling stem cell dynamics by lineage tracing. Nat Rev Mol Cell Biol. 2013;14(8):489–502.

    Article  CAS  PubMed  Google Scholar 

  83. Ousset M, Van Keymeulen A, Bouvencourt G, Sharma N, Achouri Y, Simons BD, Blanpain C. Multipotent and unipotent progenitors contribute to prostate postnatal development. Nat Cell Biol. 2012;14(11):1131–8.

    Article  CAS  PubMed  Google Scholar 

  84. Choi N, Zhang B, Zhang L, Ittmann M, Xin L. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell. 2012;21(2):253–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Beltran H, Tomlins S, Aparicio A, Arora V, Rickman D, Ayala G, Huang J, True L, Gleave ME, Soule H, Logothetis C, Rubin MA. Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res. 2014;20(11):2846–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Halabi S, Kelly WK, Ma H, Zhou H, Solomon NC, Fizazi K, Tangen CM, Rosenthal M, Petrylak DP, Hussain M, Vogelzang NJ, Thompson IM, Chi KN, de Bono J, Armstrong AJ, Eisenberger MA, Fandi A, Li S, Araujo JC, Logothetis CJ, Quinn DI, Morris MJ, Higano CS, Tannock IF, Small EJ. Meta-analysis evaluating the impact of site of metastasis on overall survival in men with castration-resistant prostate cancer. J Clin Oncol. 2016;34(14):1652–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009;9(4):302–12.

    Article  CAS  PubMed  Google Scholar 

  88. Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol. 1974;111(1):58–64.

    Article  CAS  PubMed  Google Scholar 

  89. Amin MB, Epstein JI, Ulbright TM, Humphrey PA, Egevad L, Montironi R, Grignon D, Trpkov K, Lopez-Beltran A, Zhou M, Argani P, Delahunt B, Berney DM, Srigley JR, Tickoo SK, Reuter VE. Best practices recommendations in the application of immunohistochemistry in urologic pathology: report from the International Society of Urological Pathology consensus conference. Am J Surg Pathol. 2014;38(8):1017–22.

    Article  PubMed  Google Scholar 

  90. Turajlic S, Swanton C. Metastasis as an evolutionary process. Science. 2016;352(6282):169–75.

    Article  CAS  PubMed  Google Scholar 

  91. Kumar A, Coleman I, Morrissey C, Zhang X, True LD, Gulati R, Etzioni R, Bolouri H, Montgomery B, White T, Lucas JM, Brown LG, Dumpit RF, DeSarkar N, Higano C, Yu EY, Coleman R, Schultz N, Fang M, Lange PH, Shendure J, Vessella RL, Nelson PS. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med. 2016;22(4):369–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Network CGAR. The molecular taxonomy of primary prostate cancer. Cell. 2015;163(4):1011–25.

    Article  CAS  Google Scholar 

  93. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–28.

    Google Scholar 

  94. Hong MK, Macintyre G, Wedge DC, Van Loo P, Patel K, Lunke S, Alexandrov LB, Sloggett C, Cmero M, Marass F, Tsui D, Mangiola S, Lonie A, Naeem H, Sapre N, Phal PM, Kurganovs N, Chin X, Kerger M, Warren AY, Neal D, Gnanapragasam V, Rosenfeld N, Pedersen JS, Ryan A, Haviv I, Costello AJ, Corcoran NM, Hovens CM. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat Commun. 2015;6:6605.

    Article  CAS  PubMed  Google Scholar 

  95. Lindberg J, Kristiansen A, Wiklund P, Gronberg H, Egevad L. Tracking the origin of metastatic prostate cancer. Eur Urol. 2015;67(5):819–22.

    Article  PubMed  Google Scholar 

  96. Montironi R, Scarpelli M, Cheng L, Lopez-Beltran A, Zhou M, Montorsi F. Do not misinterpret intraductal carcinoma of the prostate as high-grade prostatic intraepithelial neoplasia! Eur Urol. 2012;62(3):518–22.

    Article  PubMed  Google Scholar 

  97. Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, Adejola N, Gurel M, Hicks J, Meeker AK, Halushka MK, Simons JW, Isaacs WB, De Marzo AM, Nelson WG, Yegnasubramanian S. Tracking the clonal origin of lethal prostate cancer. J Clin Invest. 2013;123(11):4918–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Welch HG, Gorski DH, Albertsen PC. Trends in metastatic breast and prostate cancer–lessons in cancer dynamics. N Engl J Med. 2015;373(18):1685–7.

    Article  PubMed  Google Scholar 

  99. Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmuller G, Klein CA. Systemic spread is an early step in breast cancer. Cancer Cell. 2008;13(1):58–68.

    Article  PubMed  CAS  Google Scholar 

  100. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, Kwiatkowski M, Lujan M, Lilja H, Zappa M, Denis LJ, Recker F, Paez A, Maattanen L, Bangma CH, Aus G, Carlsson S, Villers A, Rebillard X, van der Kwast T, Kujala PM, Blijenberg BG, Stenman UH, Huber A, Taari K, Hakama M, Moss SM, de Koning HJ, Auvinen A. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012;366(11):981–90.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Eyles J, Puaux AL, Wang X, Toh B, Prakash C, Hong M, Tan TG, Zheng L, Ong LC, Jin Y, Kato M, Prevost-Blondel A, Chow P, Yang H, Abastado JP. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest. 2010;120(6):2030–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ. EMT and dissemination precede pancreatic tumor formation. Cell. 2012;148(1-2):349–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Pagliarulo V, Hawes D, Brands FH, Groshen S, Cai J, Stein JP, Lieskovsky G, Skinner DG, Cote RJ. Detection of occult lymph node metastases in locally advanced node-negative prostate cancer. J Clin Oncol. 2006;24(18):2735–42.

    Article  PubMed  Google Scholar 

  104. Jachetti E, Caputo S, Mazzoleni S, Brambillasca CS, Parigi SM, Grioni M, Piras IS, Restuccia U, Calcinotto A, Freschi M, Bachi A, Galli R, Bellone M. Tenascin-C protects cancer stem-like cells from immune surveillance by arresting T-cell activation. Cancer Res. 2015;75(10):2095–108.

    Article  CAS  PubMed  Google Scholar 

  105. Jachetti E, Mazzoleni S, Grioni M, Ricupito A, Brambillasca C, Generoso L, Calcinotto A, Freschi M, Mondino A, Galli R, Bellone M. Prostate cancer stem cells are targets of both innate and adaptive immunity and elicit tumor-specific immune responses. Oncoimmunology. 2013;2(5):e24520.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Bellone M, Caputo S, Jachetti E. Immunosuppression via Tenascin-C. Oncoscience. 2015;2(8):667–8.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Plaks V, Koopman CD, Werb Z. Cancer. Circulating tumor cells. Science. 2013;341(6151):1186–8.

    Article  CAS  PubMed  Google Scholar 

  108. Massague J, Obenauf AC. Metastatic colonization by circulating tumour cells. Nature. 2016;529(7586):298–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, Ryan P, Balis UJ, Tompkins RG, Haber DA, Toner M. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 2007;450(7173):1235–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lowes LE, Hedley BD, Keeney M, Allan AL. User-defined protein marker assay development for characterization of circulating tumor cells using the CellSearch(R) system. Cytometry A. 2012;81(11):983–95.

    Article  PubMed  CAS  Google Scholar 

  111. Friedlander TW, Ngo VT, Dong H, Premasekharan G, Weinberg V, Doty S, Zhao Q, Gilbert EG, Ryan CJ, Chen WT, Paris PL. Detection and characterization of invasive circulating tumor cells derived from men with metastatic castration-resistant prostate cancer. Int J Cancer. 2014;134(10):2284–93.

    Article  CAS  PubMed  Google Scholar 

  112. Au SH, Storey BD, Moore JC, Tang Q, Chen YL, Javaid S, Sarioglu AF, Sullivan R, Madden MW, O’Keefe R, Haber DA, Maheswaran S, Langenau DM, Stott SL, Toner M. Clusters of circulating tumor cells traverse capillary-sized vessels. Proc Natl Acad Sci U S A. 2016;113(18):4947–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Brannigan BW, Kapur R, Stott SL, Shioda T, Ramaswamy S, Ting DT, Lin CP, Toner M, Haber DA, Maheswaran S. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014;158(5):1110–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351(8):781–91.

    Article  CAS  PubMed  Google Scholar 

  115. Moreno JG, Miller MC, Gross S, Allard WJ, Gomella LG, Terstappen LW. Circulating tumor cells predict survival in patients with metastatic prostate cancer. Urology. 2005;65(4):713–8.

    Article  PubMed  Google Scholar 

  116. Halabi S, Lin CY, Kelly WK, Fizazi KS, Moul JW, Kaplan EB, Morris MJ, Small EJ. Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2014;32(7):671–7.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Scher HI, Heller G, Molina A, Attard G, Danila DC, Jia X, Peng W, Sandhu SK, Olmos D, Riisnaes R, McCormack R, Burzykowski T, Kheoh T, Fleisher M, Buyse M, de Bono JS. Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer. J Clin Oncol. 2015;33(12):1348–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Lohr JG, Adalsteinsson VA, Cibulskis K, Choudhury AD, Rosenberg M, Cruz-Gordillo P, Francis JM, Zhang CZ, Shalek AK, Satija R, Trombetta JJ, Lu D, Tallapragada N, Tahirova N, Kim S, Blumenstiel B, Sougnez C, Lowe A, Wong B, Auclair D, Van Allen EM, Nakabayashi M, Lis RT, Lee GS, Li T, Chabot MS, Ly A, Taplin ME, Clancy TE, Loda M, Regev A, Meyerson M, Hahn WC, Kantoff PW, Golub TR, Getz G, Boehm JS, Love JC. Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer. Nat Biotechnol. 2014;32(5):479–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, Concannon KF, Donaldson MC, Sequist LV, Brachtel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA, Maheswaran S. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339(6119):580–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.

    Article  CAS  PubMed  Google Scholar 

  121. Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, Klein C, Saini M, Bauerle T, Wallwiener M, Holland-Letz T, Hofner T, Sprick M, Scharpff M, Marme F, Sinn HP, Pantel K, Weichert W, Trumpp A. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol. 2013;31(6):539–44.

    Article  CAS  PubMed  Google Scholar 

  122. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1(3):313–23.

    Article  CAS  PubMed  Google Scholar 

  123. Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, Kim JK, Patel LR, Ying C, Ziegler AM, Pienta MJ, Song J, Wang J, Loberg RD, Krebsbach PH, Pienta KJ, Taichman RS. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011;121(4):1298–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Shiozawa Y, Berry JE, Eber MR, Jung Y, Yumoto K, Cackowski FC, Yoon HJ, Parsana P, Mehra R, Wang J, McGee S, Lee E, Nagrath S, Pienta KJ, Taichman RS. The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer. Oncotarget. 2016;7(27):41217–32.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Gittes RF, McCullough DL. Occult carcinoma of the prostate: an oversight of immune surveillance--a working hypothesis. J Urol. 1974;112(2):241–4.

    Article  CAS  PubMed  Google Scholar 

  126. Shappell SB, Thomas GV, Roberts RL, Herbert R, Ittmann MM, Rubin MA, Humphrey PA, Sundberg JP, Rozengurt N, Barrios R, Ward JM, Cardiff RD. Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Res. 2004;64(6):2270–305.

    Article  CAS  PubMed  Google Scholar 

  127. Swanson GP, Hubbard JK. A better understanding of lymphatic drainage of the prostate with modern imaging and surgical techniques. Clin Genitourin Cancer. 2013;11(4):431–40.

    Article  PubMed  Google Scholar 

  128. Zumsteg A, Baeriswyl V, Imaizumi N, Schwendener R, Ruegg C, Christofori G. Myeloid cells contribute to tumor lymphangiogenesis. PLoS One. 2009;4(9):e7067.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Zeng Y, Opeskin K, Baldwin ME, Horvath LG, Achen MG, Stacker SA, Sutherland RL, Williams ED. Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer. Clin Cancer Res. 2004;10(15):5137–44.

    Article  CAS  PubMed  Google Scholar 

  130. Wong SY, Haack H, Crowley D, Barry M, Bronson RT, Hynes RO. Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Res. 2005;65(21):9789–98.

    Article  CAS  PubMed  Google Scholar 

  131. Mercader M, Bodner BK, Moser MT, Kwon PS, Park ES, Manecke RG, Ellis TM, Wojcik EM, Yang D, Flanigan RC, Waters WB, Kast WM, Kwon ED. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc Natl Acad Sci U S A. 2001;98(25):14565–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160(1-2):48–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S, Robbins PF, Gartner JJ, Zheng Z, Li YF, Ray S, Wunderlich JR, Somerville RP, Rosenberg SA. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science. 2015;350(6266):1387–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Borresen-Dale AL, Boyault S, Burkhardt B, Butler AP, Caldas C, Davies HR, Desmedt C, Eils R, Eyfjord JE, Foekens JA, Greaves M, Hosoda F, Hutter B, Ilicic T, Imbeaud S, Imielinski M, Jager N, Jones DT, Jones D, Knappskog S, Kool M, Lakhani SR, Lopez-Otin C, Martin S, Munshi NC, Nakamura H, Northcott PA, Pajic M, Papaemmanuil E, Paradiso A, Pearson JV, Puente XS, Raine K, Ramakrishna M, Richardson AL, Richter J, Rosenstiel P, Schlesner M, Schumacher TN, Span PN, Teague JW, Totoki Y, Tutt AN, Valdes-Mas R, van Buuren MM, van’t Veer L, Vincent-Salomon A, Waddell N, Yates LR, Zucman-Rossi J, Futreal PA, McDermott U, Lichter P, Meyerson M, Grimmond SM, Siebert R, Campo E, Shibata T, Pfister SM, Campbell PJ, Stratton MR. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Gajewski TF, Fuertes M, Spaapen R, Zheng Y, Kline J. Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment. Curr Opin Immunol. 2011;23(2):286–92.

    Article  CAS  PubMed  Google Scholar 

  138. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Bronte V, Kasic T, Gri G, Gallana K, Borsellino G, Marigo I, Battistini L, Iafrate M, Prayer-Galetti T, Pagano F, Viola A. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med. 2005;201(8):1257–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. McClinton S, Miller ID, Eremin O. An immunohistochemical characterisation of the inflammatory cell infiltrate in benign and malignant prostatic disease. Brit J Cancer. 1990;61(3):400–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Leclerc BG, Charlebois R, Chouinard G, Allard B, Pommey S, Saad F, Stagg J. CD73 expression is an independent prognostic factor in prostate cancer. Clin Cancer Res. 2016;22(1):158–66.

    Article  CAS  PubMed  Google Scholar 

  142. Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, De Palma A, Mauri P, Monegal A, Rescigno M, Savino B, Colombo P, Jonjic N, Pecanic S, Lazzarato L, Fruttero R, Gasco A, Bronte V, Viola A. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med. 2011;208(10):1949–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Drake CG, Doody AD, Mihalyo MA, Huang CT, Kelleher E, Ravi S, Hipkiss EL, Flies DB, Kennedy EP, Long M, McGary PW, Coryell L, Nelson WG, Pardoll DM, Adler AJ. Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. Cancer Cell. 2005;7(3):239–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. McArdle PA, McMillan DC, Sattar N, Wallace AM, Underwood MA. The relationship between interleukin-6 and C-reactive protein in patients with benign and malignant prostate disease. Brit J Cancer. 2004;91(10):1755–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Miller AM, Lundberg K, Ozenci V, Banham AH, Hellstrom M, Egevad L, Pisa P. CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol. 2006;177(10):7398–405.

    Article  CAS  PubMed  Google Scholar 

  146. Woo JR, Liss MA, Muldong MT, Palazzi K, Strasner A, Ammirante M, Varki N, Shabaik A, Howell S, Kane CJ, Karin M, Jamieson CA. Tumor infiltrating B-cells are increased in prostate cancer tissue. J Transl Med. 2014;12:30.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Ammirante M, Kuraishy AI, Shalapour S, Strasner A, Ramirez-Sanchez C, Zhang W, Shabaik A, Karin M. An IKKalpha-E2F1-BMI1 cascade activated by infiltrating B cells controls prostate regeneration and tumor recurrence. Genes Dev. 2013;27(13):1435–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature. 2010;464(7286):302–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Ammirante M, Shalapour S, Kang Y, Jamieson CA, Karin M. Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc Natl Acad Sci U S A. 2014;111(41):14776–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Lee GT, Kwon SJ, Lee JH, Jeon SS, Jang KT, Choi HY, Lee HM, Kim WJ, Lee DH, Kim IY. Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop. Prostate. 2011;71(14):1525–37.

    CAS  PubMed  Google Scholar 

  151. Pittoni P, Tripodo C, Piconese S, Mauri G, Parenza M, Rigoni A, Sangaletti S, Colombo MP. Mast cell targeting hampers prostate adenocarcinoma development but promotes the occurrence of highly malignant neuroendocrine cancers. Cancer Res. 2011;71(18):5987–97.

    Article  CAS  PubMed  Google Scholar 

  152. Shimura S, Yang G, Ebara S, Wheeler TM, Frolov A, Thompson TC. Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression. Cancer Res. 2000;60(20):5857–61.

    CAS  PubMed  Google Scholar 

  153. Bigotti G, Coli A, Castagnola D. Distribution of Langerhans cells and HLA class II molecules in prostatic carcinomas of different histopathological grade. Prostate. 1991;19(1):73–87.

    Article  CAS  PubMed  Google Scholar 

  154. Comito G, Giannoni E, Segura CP, Barcellos-de-Souza P, Raspollini MR, Baroni G, Lanciotti M, Serni S, Chiarugi P. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene. 2014;33(19):2423–31.

    Article  CAS  PubMed  Google Scholar 

  155. Soki FN, Koh AJ, Jones JD, Kim YW, Dai J, Keller ET, Pienta KJ, Atabai K, Roca H, McCauley LK. Polarization of prostate cancer-associated macrophages is induced by milk fat globule-EGF factor 8 (MFG-E8)-mediated efferocytosis. J Biol Chem. 2014;289(35):24560–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Lundholm M, Hagglof C, Wikberg ML, Stattin P, Egevad L, Bergh A, Wikstrom P, Palmqvist R, Edin S. Secreted factors from colorectal and prostate cancer cells skew the immune response in opposite directions. Sci Rep. 2015;5:15651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Miller AM, Pisa P. Tumor escape mechanisms in prostate cancer. Cancer Immunol Immunother. 2007;56(1):81–7.

    Article  CAS  PubMed  Google Scholar 

  158. Kusmartsev S, Vieweg J. Enhancing the efficacy of cancer vaccines in urologic oncology: new directions. Nat Rev Urol. 2009;6(10):540–9.

    Article  CAS  PubMed  Google Scholar 

  159. Mellor AL, Munn DH. Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat Rev Immunol. 2008;8(1):74–80.

    Article  CAS  PubMed  Google Scholar 

  160. Rigamonti N, Bellone M. Prostate cancer, tumor immunity and a renewed sense of optimism in immunotherapy. Cancer Immunol Immunother. 2012;61(4):453–68.

    Article  CAS  PubMed  Google Scholar 

  161. Derhovanessian E, Adams V, Hahnel K, Groeger A, Pandha H, Ward S, Pawelec G. Pretreatment frequency of circulating IL-17+ CD4+ T-cells, but not Tregs, correlates with clinical response to whole-cell vaccination in prostate cancer patients. Int J Cancer. 2009;125(6):1372–9.

    Article  CAS  PubMed  Google Scholar 

  162. Sfanos KS, Bruno TC, Maris CH, Xu L, Thoburn CJ, DeMarzo AM, Meeker AK, Isaacs WB, Drake CG. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res. 2008;14(11):3254–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Burbridge S, Goldstein RM, Cahill D, Chowdhury S, Maher J. Role of lymphotoxin-a and interleukin-17A in human prostate cancer. J Clin Oncol. 2012;30(5_suppl):212.

    Article  Google Scholar 

  164. Degl’Innocenti E, Grioni M, Capuano G, Jachetti E, Freschi M, Bertilaccio MT, Hess-Michelini R, Doglioni C, Bellone M. Peripheral T-cell tolerance associated with prostate cancer is independent from CD4+CD25+ regulatory T cells. Cancer Res. 2008;68(1):292–300.

    Article  PubMed  CAS  Google Scholar 

  165. Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, Amit AS, Kang C, Geddes JE, Allison JP, Socci ND, Savage PA. Aire-dependent thymic development of tumor-associated regulatory T cells. Science. 2013;339(6124):1219–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Hadaschik B, Su Y, Huter E, Ge Y, Hohenfellner M, Beckhove P. Antigen specific T-cell responses against tumor antigens are controlled by regulatory T cells in patients with prostate cancer. J Urol. 2012;187(4):1458–65.

    Article  CAS  PubMed  Google Scholar 

  167. Getnet D, Maris CH, Hipkiss EL, Grosso JF, Harris TJ, Yen HR, Bruno TC, Wada S, Adler A, Georgantas RW, Jie C, Goldberg MV, Pardoll DM, Drake CG. Tumor recognition and self-recognition induce distinct transcriptional profiles in antigen-specific CD4 T cells. J Immunol. 2009;182(8):4675–85.

    Article  CAS  PubMed  Google Scholar 

  168. Sorrentino C, Musiani P, Pompa P, Cipollone G, Di Carlo E. Androgen deprivation boosts prostatic infiltration of cytotoxic and regulatory T lymphocytes and has no effect on disease-free survival in prostate cancer patients. Clin Cancer Res. 2011;17(6):1571–81.

    Article  CAS  PubMed  Google Scholar 

  169. Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Rutkowski MR, Svoronos N, Perales-Puchalt A, Conejo-Garcia JR. The tumor macroenvironment: cancer-promoting networks beyond tumor beds. Adv Cancer Res. 2015;128:235–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Talmadge JE, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat Rev Cancer. 2013;13(10):739–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ostrand-Rosenberg S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother. 2010;59(10):1593–600.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Hossain DM, Pal SK, Moreira D, Duttagupta P, Zhang Q, Won H, Jones J, D’Apuzzo M, Forman S, Kortylewski M. TLR9-targeted STAT3 silencing abrogates immunosuppressive activity of myeloid-derived suppressor cells from prostate cancer patients. Clin Cancer Res. 2015;21(16):3771–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Vuk-Pavlovic S, Bulur PA, Lin Y, Qin R, Szumlanski CL, Zhao X, Dietz AB. Immunosuppressive CD14+HLA-DRlow/- monocytes in prostate cancer. Prostate. 2010;70(4):443–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Brusa D, Carletto S, Cucchiarale G, Gontero P, Greco A, Simone M, Ferrando U, Tizzani A, Matera L. Prostatectomy restores the maturation competence of blood dendritic cell precursors and reverses the abnormal expansion of regulatory T lymphocytes. Prostate. 2011;71(4):344–52.

    Article  CAS  PubMed  Google Scholar 

  176. Brusa D, Simone M, Gontero P, Spadi R, Racca P, Micari J, Degiuli M, Carletto S, Tizzani A, Matera L. Circulating immunosuppressive cells of prostate cancer patients before and after radical prostatectomy: profile comparison. Int J Urol. 2013;20(10):971–8.

    CAS  PubMed  Google Scholar 

  177. Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, Fang Z, Zhao K, Konaparthi R, Hua S, Zhang J, Li-Ning-Tapia EM, Kapoor A, Wu CJ, Patel NB, Guo Z, Ramamoorthy V, Tieu TN, Heffernan T, Zhao D, Shang X, Khadka S, Hou P, Hu B, Jin EJ, Yao W, Pan X, Ding Z, Shi Y, Li L, Chang Q, Troncoso P, Logothetis CJ, McArthur MJ, Chin L, Wang YA, DePinho RA. Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov. 2016;6(1):80–95.

    Article  PubMed  CAS  Google Scholar 

  178. Rigamonti N, Capuano G, Ricupito A, Jachetti E, Grioni M, Generoso L, Freschi M, Bellone M. Modulators of arginine metabolism do not impact on peripheral T-cell tolerance and disease progression in a model of spontaneous prostate cancer. Clin Cancer Res. 2011;17(5):1012–23.

    Article  CAS  PubMed  Google Scholar 

  179. Tahir SM, Cheng O, Shaulov A, Koezuka Y, Bubley GJ, Wilson SB, Balk SP, Exley MA. Loss of IFN-gamma production by invariant NK T cells in advanced cancer. J Immunol. 2001;167(7):4046–50.

    Article  CAS  PubMed  Google Scholar 

  180. Nowak M, Arredouani MS, Tun-Kyi A, Schmidt-Wolf I, Sanda MG, Balk SP, Exley MA. Defective NKT cell activation by CD1d+ TRAMP prostate tumor cells is corrected by interleukin-12 with alpha-galactosylceramide. PLoS One. 2010;5(6):e11311.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Bellone M, Ceccon M, Grioni M, Jachetti E, Calcinotto A, Napolitano A, Freschi M, Casorati G, Dellabona P. iNKT cells control mouse spontaneous carcinoma independently of tumor-specific cytotoxic T cells. PLoS One. 2010;5(1):e8646.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Roth TJ, Sheinin Y, Lohse CM, Kuntz SM, Frigola X, Inman BA, Krambeck AE, McKenney ME, Karnes RJ, Blute ML, Cheville JC, Sebo TJ, Kwon ED. B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy. Cancer Res. 2007;67(16):7893–900.

    Article  CAS  PubMed  Google Scholar 

  183. Crane CA, Panner A, Murray JC, Wilson SP, Xu H, Chen L, Simko JP, Waldman FM, Pieper RO, Parsa AT. PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene. 2009;28(2):306–12.

    Article  CAS  PubMed  Google Scholar 

  184. Martin AM, Nirschl TR, Nirschl CJ, Francica BJ, Kochel CM, van Bokhoven A, Meeker AK, Lucia MS, Anders RA, DeMarzo AM, Drake CG. Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance. Prostate Cancer Prostatic Dis. 2015;18(4):325–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Gevensleben H, Dietrich D, Golletz C, Steiner S, Jung M, Thiesler T, Majores M, Stein J, Uhl B, Muller S, Ellinger J, Stephan C, Jung K, Brossart P, Kristiansen G. The immune checkpoint regulator PD-L1 is highly expressed in aggressive primary prostate cancer. Clin Cancer Res. 2016;22(8):1969–77.

    Article  CAS  PubMed  Google Scholar 

  186. Goltz D, Holmes EE, Gevensleben H, Sailer V, Dietrich J, Jung M, Rohler M, Meller S, Ellinger J, Kristiansen G, Dietrich D. CXCL12 promoter methylation and PD-L1 expression as prognostic biomarkers in prostate cancer patients. Oncotarget. 2016;7(33):53309–20.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Sfanos KS, Bruno TC, Meeker AK, De Marzo AM, Isaacs WB, Drake CG. Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+. Prostate. 2009;69(15):1694–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Ebelt K, Babaryka G, Frankenberger B, Stief CG, Eisenmenger W, Kirchner T, Schendel DJ, Noessner E. Prostate cancer lesions are surrounded by FOXP3+, PD-1+ and B7-H1+ lymphocyte clusters. Eur J Cancer. 2009;45(9):1664–72.

    Article  CAS  PubMed  Google Scholar 

  189. Bellone M, Parigi SM, Jachetti E. Pre-clinical evalutation of immunotherapy: the case for prostate cancer and the TRAMP model. In: Rees RC, editor. Tumor immunology and Immunotherapy. Oxford, United Kindgdom: Oxford University Press; 2014. p. 173–89.

    Google Scholar 

  190. Drukker M, Katz G, Urbach A, Schuldiner M, Markel G, Itskovitz-Eldor J, Reubinoff B, Mandelboim O, Benvenisty N. Characterization of the expression of MHC proteins in human embryonic stem cells. Proc Natl Acad Sci U S A. 2002;99(15):9864–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Favier B, LeMaoult J, Rouas-Freiss N, Moreau P, Menier C, Carosella ED. Research on HLA-G: an update. Tissue Antigens. 2007;69(3):207–11.

    Article  CAS  PubMed  Google Scholar 

  192. Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells. 2006;24(2):386–98.

    Article  CAS  PubMed  Google Scholar 

  193. Le Blanc K. Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy. 2003;5(6):485–9.

    Article  PubMed  Google Scholar 

  194. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31(10):890–6.

    Article  PubMed  CAS  Google Scholar 

  195. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815–22.

    Article  CAS  PubMed  Google Scholar 

  196. Harris SG, Padilla J, Koumas L, Ray D, Phipps RP. Prostaglandins as modulators of immunity. Trends Immunol. 2002;23(3):144–50.

    Article  CAS  PubMed  Google Scholar 

  197. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838–43.

    Article  PubMed  Google Scholar 

  198. Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood. 2004;103(12):4619–21.

    Article  CAS  PubMed  Google Scholar 

  199. Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, Kogadeeva M, Picotti P, Meissner F, Mann M, Zamboni N, Sallusto F, Lanzavecchia A. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell. 2016;167(3):829–2 e813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Bai L, Lennon DP, Caplan AI, DeChant A, Hecker J, Kranso J, Zaremba A, Miller RH. Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Nat Neurosci. 2012;15(6):862–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Benkhoucha M, Santiago-Raber ML, Schneiter G, Chofflon M, Funakoshi H, Nakamura T, Lalive PH. Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A. 2010;107(14):6424–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, Borg C, Saas P, Tiberghien P, Rouas-Freiss N, Carosella ED, Deschaseaux F. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells. 2008;26(1):212–22.

    Article  CAS  PubMed  Google Scholar 

  203. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood. 2003;101(9):3722–9.

    Article  CAS  PubMed  Google Scholar 

  204. Maitra B, Szekely E, Gjini K, Laughlin MJ, Dennis J, Haynesworth SE, Koc ON. Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplant. 2004;33(6):597–604.

    Article  CAS  PubMed  Google Scholar 

  205. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 2003;75(3):389–97.

    Article  CAS  PubMed  Google Scholar 

  206. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11(3):259–73.

    Article  CAS  PubMed  Google Scholar 

  207. Kawasaki BT, Farrar WL. Cancer stem cells, CD200 and immunoevasion. Trends Immunol. 2008;29(10):464–8.

    Article  CAS  PubMed  Google Scholar 

  208. Di Tomaso T, Mazzoleni S, Wang E, Sovena G, Clavenna D, Franzin A, Mortini P, Ferrone S, Doglioni C, Marincola FM, Galli R, Parmiani G, Maccalli C. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin Cancer Res. 2010;16(3):800–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Wei J, Barr J, Kong LY, Wang Y, Wu A, Sharma AK, Gumin J, Henry V, Colman H, Priebe W, Sawaya R, Lang FF, Heimberger AB. Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. Mol Cancer Ther. 2010;9(1):67–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Schatton T, Schutte U, Frank NY, Zhan Q, Hoerning A, Robles SC, Zhou J, Hodi FS, Spagnoli GC, Murphy GF, Frank MH. Modulation of T-cell activation by malignant melanoma initiating cells. Cancer Res. 2010;70(2):697–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Yamashina T, Baghdadi M, Yoneda A, Kinoshita I, Suzu S, Dosaka-Akita H, Jinushi M. Cancer stem-like cells derived from chemoresistant tumors have a unique capacity to prime tumorigenic myeloid cells. Cancer Res. 2014;74(10):2698–709.

    Article  CAS  PubMed  Google Scholar 

  212. Cui TX, Kryczek I, Zhao L, Zhao E, Kuick R, Roh MH, Vatan L, Szeliga W, Mao Y, Thomas DG, Kotarski J, Tarkowski R, Wicha M, Cho K, Giordano T, Liu R, Zou W. Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity. 2013;39(3):611–21.

    Article  CAS  PubMed  Google Scholar 

  213. Eyler CE, Wu Q, Yan K, MacSwords JM, Chandler-Militello D, Misuraca KL, Lathia JD, Forrester MT, Lee J, Stamler JS, Goldman SA, Bredel M, McLendon RE, Sloan AE, Hjelmeland AB, Rich JN. Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2. Cell. 2011;146(1):53–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Volonte A, Di Tomaso T, Spinelli M, Todaro M, Sanvito F, Albarello L, Bissolati M, Ghirardelli L, Orsenigo E, Ferrone S, Doglioni C, Stassi G, Dellabona P, Staudacher C, Parmiani G, Maccalli C. Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4. J Immunol. 2014;192(1):523–32.

    Article  CAS  PubMed  Google Scholar 

  215. Koller FL, Hwang DG, Dozier EA, Fingleton B. Epithelial interleukin-4 receptor expression promotes colon tumor growth. Carcinogenesis. 2010;31(6):1010–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, Tripodo C, Russo A, Gulotta G, Medema JP, Stassi G. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1(4):389–402.

    Article  CAS  PubMed  Google Scholar 

  217. Bronte V, Serafini P, De Santo C, Marigo I, Tosello V, Mazzoni A, Segal DM, Staib C, Lowel M, Sutter G, Colombo MP, Zanovello P. IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol. 2003;170(1):270–8.

    Article  CAS  PubMed  Google Scholar 

  218. Rodolfo M, Zilocchi C, Accornero P, Cappetti B, Arioli I, Colombo MP. IL-4-transduced tumor cell vaccine induces immunoregulatory type 2 CD8 T lymphocytes that cure lung metastases upon adoptive transfer. J Immunol. 1999;163(4):1923–8.

    CAS  PubMed  Google Scholar 

  219. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan RC. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993;90(8):3539–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Arienti F, Belli F, Napolitano F, Sule-Suso J, Mazzocchi A, Gallino GF, Cattelan A, Santantonio C, Rivoltini L, Melani C, Colombo MP, Cascinelli N, Maio M, Parmiani G. Vaccination of melanoma patients with interleukin 4 gene-transduced allogeneic melanoma cells. Hum Gene Ther. 1999;10(18):2907–16.

    Article  CAS  PubMed  Google Scholar 

  221. Maio M, Fonsatti E, Lamaj E, Altomonte M, Cattarossi I, Santantonio C, Melani C, Belli F, Arienti F, Colombo MP, Parmiani G. Vaccination of stage IV patients with allogeneic IL-4- or IL-2-gene-transduced melanoma cells generates functional antibodies against vaccinating and autologous melanoma cells. Cancer Immunol Immunother. 2002;51(1):9–14.

    Article  CAS  PubMed  Google Scholar 

  222. Kozlowska AK, Tseng HC, Kaur K, Topchyan P, Inagaki A, Bui VT, Kasahara N, Cacalano N, Jewett A. Resistance to cytotoxicity and sustained release of interleukin-6 and interleukin-8 in the presence of decreased interferon-gamma after differentiation of glioblastoma by human natural killer cells. Cancer Immunol Immunother. 2016;65(9):1085–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Tuccitto A, Tazzari M, Beretta V, Rini F, Miranda C, Greco A, Santinami M, Patuzzo R, Vergani B, Villa A, Manenti G, Cleris L, Giardiello D, Alison M, Rivoltini L, Castelli C, Perego M. Immunomodulatory factors control the fate of melanoma tumor initiating cells. Stem Cells. 2016;34(10):2449–60.

    Article  CAS  PubMed  Google Scholar 

  224. Barkan D, Green JE, Chambers AF. Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth. Eur J Cancer. 2010;46(7):1181–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Giancotti FG. Mechanisms governing metastatic dormancy and reactivation. Cell. 2013;155(4):750–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 2014;15(12):1243–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Oskarsson T, Batlle E, Massague J. Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell. 2014;14(3):306–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Ruegg CR, Chiquet-Ehrismann R, Alkan SS. Tenascin, an extracellular matrix protein, exerts immunomodulatory activities. Proc Natl Acad Sci U S A. 1989;86(19):7437–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG, Downey RJ, Manova-Todorova K, Brogi E, Massague J. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med. 2011;17(7):867–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Chiquet-Ehrismann R, Orend G, Chiquet M, Tucker RP, Midwood KS. Tenascins in stem cell niches. Matrix Biol. 2014;37:112–23.

    Article  CAS  PubMed  Google Scholar 

  231. Lateef N, Abdul Basit K, Abbasi N, Kazmi SM, Ansari AB, Shah M. Malignancies after heart transplant. Exp Clin Transplant. 2016;14(1):12–6.

    PubMed  Google Scholar 

  232. di Capua Sacoto C, Lujan Marco S, Bahilo Mateu P, Budia Alba A, Pontones Moreno JL, Jimenez Cruz JF. De novo urological neoplasms in kidney transplant patients: experience in 1,751 patients. Actas Urol Esp. 2010;34(1):88–94.

    Article  PubMed  Google Scholar 

  233. Longo DL. New therapies for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):479–81.

    Article  CAS  PubMed  Google Scholar 

  234. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22.

    Article  CAS  PubMed  Google Scholar 

  235. Sheikh N, Cham J, Zhang L, DeVries T, Letarte S, Pufnock J, Hamm D, Trager J, Fong L. Clonotypic diversification of intratumoral T cells following sipuleucel-T treatment in prostate cancer subjects. Cancer Res. 2016;76(13):3711–8.

    Article  CAS  PubMed  Google Scholar 

  236. GuhaThakurta D, Sheikh NA, Fan LQ, Kandadi H, Meagher TC, Hall SJ, Kantoff PW, Higano CS, Small EJ, Gardner TA, Bailey K, Vu T, DeVries T, Whitmore JB, Frohlich MW, Trager JB, Drake CG. Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcome. Clin Cancer Res. 2015;21(16):3619–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Small EJ, Lance RS, Gardner TA, Karsh LI, Fong L, McCoy C, DeVries T, Sheikh NA, GuhaThakurta D, Chang N, Redfern CH, Shore ND. A randomized phase II trial of sipuleucel-T with concurrent versus sequential abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2015;21(17):3862–9.

    Article  CAS  PubMed  Google Scholar 

  238. Le DT, Pardoll DM, Jaffee EM. Cellular vaccine approaches. Cancer J. 2010;16(4):304–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Madan RA, Arlen PM, Mohebtash M, Hodge JW, Gulley JL. Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs. 2009;18(7):1001–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Karan D, Holzbeierlein JM, Van Veldhuizen P, Thrasher JB. Cancer immunotherapy: a paradigm shift for prostate cancer treatment. Nat Rev Urol. 2012;9(7):376–85.

    Article  CAS  PubMed  Google Scholar 

  241. Klebanoff CA, Rosenberg SA, Restifo NP. Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat Med. 2016;22(1):26–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Salama AK, Hodi FS. Cytotoxic T-lymphocyte-associated antigen-4. Clin Cancer Res. 2011;17(14):4622–8.

    Article  CAS  PubMed  Google Scholar 

  244. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.

    Article  CAS  PubMed  Google Scholar 

  245. Hurwitz AA, Foster BA, Kwon ED, Truong T, Choi EM, Greenberg NM, Burg MB, Allison JP. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res. 2000;60(9):2444–8.

    CAS  PubMed  Google Scholar 

  246. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengelov L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Modena A, Ciccarese C, Iacovelli R, Brunelli M, Montironi R, Fiorentino M, Tortora G, Massari F. Immune checkpoint inhibitors and prostate cancer: a new frontier? Oncol Rev. 2016;10(1):293.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

    Article  CAS  PubMed  Google Scholar 

  249. Castriconi R, Dondero A, Negri F, Bellora F, Nozza P, Carnemolla B, Raso A, Moretta L, Moretta A, Bottino C. Both CD133+ and CD133- medulloblastoma cell lines express ligands for triggering NK receptors and are susceptible to NK-mediated cytotoxicity. Eur J Immunol. 2007;37(11):3190–6.

    Article  CAS  PubMed  Google Scholar 

  250. Castriconi R, Daga A, Dondero A, Zona G, Poliani PL, Melotti A, Griffero F, Marubbi D, Spaziante R, Bellora F, Moretta L, Moretta A, Corte G, Bottino C. NK cells recognize and kill human glioblastoma cells with stem cell-like properties. J Immunol. 2009;182(6):3530–9.

    Article  CAS  PubMed  Google Scholar 

  251. Todaro M, D’Asaro M, Caccamo N, Iovino F, Francipane MG, Meraviglia S, Orlando V, La Mendola C, Gulotta G, Salerno A, Dieli F, Stassi G. Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes. J Immunol. 2009;182(11):7287–96.

    Article  CAS  PubMed  Google Scholar 

  252. Pietra G, Manzini C, Vitale M, Balsamo M, Ognio E, Boitano M, Queirolo P, Moretta L, Mingari MC. Natural killer cells kill human melanoma cells with characteristics of cancer stem cells. Int Immunol. 2009;21(7):793–801.

    Article  CAS  PubMed  Google Scholar 

  253. Brown CE, Starr R, Martinez C, Aguilar B, D’Apuzzo M, Todorov I, Shih CC, Badie B, Hudecek M, Riddell SR, Jensen MC. Recognition and killing of brain tumor stem-like initiating cells by CD8+ cytolytic T cells. Cancer Res. 2009;69(23):8886–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Pellegatta S, Poliani PL, Corno D, Menghi F, Ghielmetti F, Suarez-Merino B, Caldera V, Nava S, Ravanini M, Facchetti F, Bruzzone MG, Finocchiaro G. Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Res. 2006;66(21):10247–52.

    Article  CAS  PubMed  Google Scholar 

  255. Xu QJ, Liu GT, Yuan XP, Xu ML, Wang HQ, Ji JF, Konda B, Black KL, Yu JS. Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens. Stem Cells. 2009;27(8):1734–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Parmiani G, Russo V, Marrari A, Cutolo G, Casati C, Pilla L, Maccalli C, Rivoltini L, Castelli C. Universal and stemness-related tumor antigens: potential use in cancer immunotherapy. Clin Cancer Res. 2007;13(19):5675–9.

    Article  CAS  PubMed  Google Scholar 

  257. Visus C, Wang Y, Lozano-Leon A, Ferris RL, Silver S, Szczepanski MJ, Brand RE, Ferrone CR, Whiteside TL, Ferrone S, DeLeo AB, Wang X. Targeting ALDH(bright) human carcinoma-initiating cells with ALDH1A1-specific CD8(+) T cells. Clin Cancer Res. 2011;17(19):6174–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Maccalli C, Volonte A, Cimminiello C, Parmiani G. Immunology of cancer stem cells in solid tumours. A review. Eur J Cancer. 2014;50(3):649–55.

    Article  CAS  PubMed  Google Scholar 

  259. Schmitz M, Temme A, Senner V, Ebner R, Schwind S, Stevanovic S, Wehner R, Schackert G, Schackert HK, Fussel M, Bachmann M, Rieber EP, Weigle B. Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy (vol 96, pg 1293, 2007). Brit J Cancer. 2007;96(12):1928.

    Article  CAS  PubMed Central  Google Scholar 

  260. Hua W, Yao Y, Chu YW, Zhong P, Sheng XF, Xiao BG, Wu JS, Yang BJ, Mao Y, Zhou LF. The CD133+ tumor stem-like cell-associated antigen may elicit highly intense immune responses against human malignant glioma. J Neuro-Oncol. 2011;105(2):149–57.

    Article  CAS  Google Scholar 

  261. Mitra M, Kandalam M, Harilal A, Verma RS, Krishnan UM, Swaminathan S, Krishnakumar S. EpCAM is a putative stem marker in retinoblastoma and an effective target for T-cell-mediated immunotherapy. Mol Vis. 2012;18(31–33):290–308.

    CAS  PubMed  PubMed Central  Google Scholar 

  262. Inoda S, Hirohashi Y, Torigoe T, Morita R, Takahashi A, Asanuma H, Nakatsugawa M, Nishizawa S, Tamura Y, Tsuruma T, Terui T, Kondo T, Ishitani K, Hasegawa T, Hirata K, Sato N. Cytotoxic T lymphocytes efficiently recognize human colon cancer stem-like cells. Am J Pathol. 2011;178(4):1805–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Stratford EW, Bostad M, Castro R, Skarpen E, Berg K, Hogset A, Myklebost O, Selbo PK. Photochemical internalization of CD133-targeting immunotoxins efficiently depletes sarcoma cells with stem-like properties and reduces tumorigenicity. Biochim Biophys Acta. 2013;1830(8):4235–43.

    Article  CAS  PubMed  Google Scholar 

  264. Huang J, Li C, Wang Y, Lv H, Guo Y, Dai H, Wicha MS, Chang AE, Li Q. Cytokine-induced killer (CIK) cells bound with anti-CD3/anti-CD133 bispecific antibodies target CD133(high) cancer stem cells in vitro and in vivo. Clin Immunol. 2013;149(1):156–68.

    Article  CAS  PubMed  Google Scholar 

  265. Pan Q, Li Q, Liu S, Ning N, Zhang XL, Xu YX, Chang AE, Wicha MS. Concise review: targeting cancer stem cells using immunologic approaches. Stem Cells. 2015;33(7):2085–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Swaminathan SK, Roger E, Toti U, Niu L, Ohlfest JR, Panyam J. CD133-targeted paclitaxel delivery inhibits local tumor recurrence in a mouse model of breast cancer. J Control Release. 2013;171(3):280–7.

    Article  CAS  PubMed  Google Scholar 

  267. Skubitz AP, Taras EP, Boylan KL, Waldron NN, Oh S, Panoskaltsis-Mortari A, Vallera DA. Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression. Gynecol Oncol. 2013;130(3):579–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Li L, Tang W, Wu X, Karnak D, Meng X, Thompson R, Hao X, Li Y, Qiao XT, Lin J, Fuchs J, Simeone DM, Chen ZN, Lawrence TS, Xu L. HAb18G/CD147 promotes pSTAT3-mediated pancreatic cancer development via CD44s. Clin Cancer Res. 2013;19(24):6703–15.

    Article  CAS  PubMed  Google Scholar 

  269. Draffin JE, McFarlane S, Hill A, Johnston PG, Waugh DJ. CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res. 2004;64(16):5702–11.

    Article  CAS  PubMed  Google Scholar 

  270. Liu AY, True LD, LaTray L, Ellis WJ, Vessella RL, Lange PH, Higano CS, Hood L, van den Engh G. Analysis and sorting of prostate cancer cell types by flow cytometry. Prostate. 1999;40(3):192–9.

    Article  PubMed  Google Scholar 

  271. Yun EJ, Zhou J, Lin CJ, Hernandez E, Fazli L, Gleave M, Hsieh JT. Targeting cancer stem cells in castration-resistant prostate cancer. Clin Cancer Res. 2016;22(3):670–9.

    Article  CAS  PubMed  Google Scholar 

  272. Salanti A, Clausen TM, Agerbaek MO, Al Nakouzi N, Dahlback M, Oo HZ, Lee S, Gustavsson T, Rich JR, Hedberg BJ, Mao Y, Barington L, Pereira MA, LoBello J, Endo M, Fazli L, Soden J, Wang CK, Sander AF, Dagil R, Thrane S, Holst PJ, Meng L, Favero F, Weiss GJ, Nielsen MA, Freeth J, Nielsen TO, Zaia J, Tran NL, Trent J, Babcook JS, Theander TG, Sorensen PH, Daugaard M. Targeting human cancer by a glycosaminoglycan binding malaria protein. Cancer Cell. 2015;28(4):500–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Huang WY, Lin JN, Hsieh JT, Chou SC, Lai CH, Yun EJ, Lo UG, Pong RC, Lin JH, Lin YH. Nanoparticle targeting CD44-positive cancer cells for site-specific drug delivery in prostate cancer therapy. ACS Appl Mater Interfaces. 2016;8(45):30722–34.

    Article  CAS  PubMed  Google Scholar 

  274. Welsh CF, Zhu D, Bourguignon LY. Interaction of CD44 variant isoforms with hyaluronic acid and the cytoskeleton in human prostate cancer cells. J Cell Physiol. 1995;164(3):605–12.

    Article  CAS  PubMed  Google Scholar 

  275. Casucci M, Nicolis di Robilant B, Falcone L, Camisa B, Norelli M, Genovese P, Gentner B, Gullotta F, Ponzoni M, Bernardi M, Marcatti M, Saudemont A, Bordignon C, Savoldo B, Ciceri F, Naldini L, Dotti G, Bonini C, Bondanza A. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood. 2013;122(20):3461–72.

    Article  CAS  PubMed  Google Scholar 

  276. Reiter RE, Gu Z, Watabe T, Thomas G, Szigeti K, Davis E, Wahl M, Nisitani S, Yamashiro J, Le Beau MM, Loda M, Witte ON. Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc Natl Acad Sci U S A. 1998;95(4):1735–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Saffran DC, Raitano AB, Hubert RS, Witte ON, Reiter RE, Jakobovits A. Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts. Proc Natl Acad Sci U S A. 2001;98(5):2658–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Thomas-Kaskell AK, Zeiser R, Jochim R, Robbel C, Schultze-Seemann W, Waller CF, Veelken H. Vaccination of advanced prostate cancer patients with PSCA and PSA peptide-loaded dendritic cells induces DTH responses that correlate with superior overall survival. Int J Cancer. 2006;119(10):2428–34.

    Article  CAS  Google Scholar 

  279. Waeckerle-Men Y, Uetz-von Allmen E, Fopp M, von Moos R, Bohme C, Schmid HP, Ackermann D, Cerny T, Ludewig B, Groettrup M, Gillessen S. Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma. Cancer Immunol Immun. 2006;55(12):1524–33.

    Article  Google Scholar 

  280. Morgenroth A, Cartellieri M, Schmitz M, Gunes S, Weigle B, Bachmann M, Abken H, Rieber EP, Temme A. Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) using genetically engineered T-cells. Prostate. 2007;67(10):1121–31.

    Article  CAS  PubMed  Google Scholar 

  281. Cartellieri M, Koristka S, Arndt C, Feldmann A, Stamova S, von Bonin M, Topfer K, Kruger T, Geib M, Michalk I, Temme A, Bornhauser M, Lindemann D, Ehninger G, Bachmann MP. A novel ex vivo isolation and expansion procedure for chimeric antigen receptor engrafted human T cells. PLoS One. 2014;9(4):e93745.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  282. Abate-Daga D, Lagisetty KH, Tran E, Zheng Z, Gattinoni L, Yu Z, Burns WR, Miermont AM, Teper Y, Rudloff U, Restifo NP, Feldman SA, Rosenberg SA, Morgan RA. A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer. Hum Gene Ther. 2014;25(12):1003–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Ni J, Cozzi PJ, Duan W, Shigdar S, Graham PH, John KH, Li Y. Role of the EpCAM (CD326) in prostate cancer metastasis and progression. Cancer Metastasis Rev. 2012;31(3-4):779–91.

    Article  CAS  PubMed  Google Scholar 

  284. Ni J, Cozzi P, Hao JL, Beretov J, Chang L, Duan W, Shigdar S, Delprado W, Graham P, Bucci J, Kearsley J, Li Y. Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway. Int J Biochem Cell B. 2013;45(12):2736–48.

    Article  CAS  Google Scholar 

  285. Deng Z, Wu Y, Ma W, Zhang S, Zhang YQ. Adoptive T-cell therapy of prostate cancer targeting the cancer stem cell antigen EpCAM. BMC Immunol. 2015;16:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Wong N, Major P, Kapoor A, Wei F, Yan J, Aziz T, Zheng M, Jayasekera D, Cutz JC, Chow MJ, Tang D. Amplification of MUC1 in prostate cancer metastasis and CRPC development. Oncotarget. 2016;7(50):83115–33.

    Article  PubMed  PubMed Central  Google Scholar 

  287. Scheid E, Major P, Bergeron A, Finn OJ, Salter RD, Eady R, Yassine-Diab B, Favre D, Peretz Y, Landry C, Hotte S, Mukherjee SD, Dekaban GA, Fink C, Foster PJ, Gaudet J, Gariepy J, Sekaly RP, Lacombe L, Fradet Y, Foley R. Tn-MUC1 DC vaccination of rhesus macaques and a phase I/II trial in patients with nonmetastatic castrate-resistant prostate cancer. Cancer Immunol Res. 2016;4(10):881–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Brichard VG, Lejeune D. Cancer immunotherapy targeting tumour-specific antigens: towards a new therapy for minimal residual disease. Expert Opin Biol Ther. 2008;8(7):951–68.

    Article  CAS  PubMed  Google Scholar 

  289. Degl’Innocenti E, Grioni M, Boni A, Camporeale A, Bertilaccio MTS, Freschi M, Monno A, Arcelloni C, Greenberg NM, Bellone M. Peripheral T cell tolerance occurs early during spontaneous prostate cancer development and can be rescued by dendritic cell immunization. Eur J Immunol. 2005;35(1):66–75.

    Article  PubMed  CAS  Google Scholar 

  290. Chang AJ, Autio KA, Roach M, Scher HI. High-risk prostate cancer-classification and therapy. Nat Rev Clin Oncol. 2014;11(6):308–23.

    Article  PubMed  PubMed Central  Google Scholar 

  291. Nagabhushan M, Pretlow TG, Guo YJ, Amini SB, Pretlow TP, Sy MS. Altered expression of CD44 in human prostate cancer during progression. Am J Clin Pathol. 1996;106(5):647–51.

    Article  CAS  PubMed  Google Scholar 

  292. Noordzij MA, van Steenbrugge GJ, Verkaik NS, Schroder FH, van der Kwast TH. The prognostic value of CD44 isoforms in prostate cancer patients treated by radical prostatectomy. Clin Cancer Res. 1997;3(5):805–15.

    CAS  PubMed  Google Scholar 

  293. Hernandez JR, Kim JJ, Verdone JE, Liu X, Torga G, Pienta KJ, Mooney SM. Alternative CD44 splicing identifies epithelial prostate cancer cells from the mesenchymal counterparts. Med Oncol. 2015;32(5):159.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  294. De Marzo AM, Bradshaw C, Sauvageot J, Epstein JI, Miller GJ. CD44 and CD44v6 downregulation in clinical prostatic carcinoma: relation to Gleason grade and cytoarchitecture. Prostate. 1998;34(3):162–8.

    Article  PubMed  Google Scholar 

  295. Aaltomaa S, Lipponen P, Viitanen J, Kankkunen JP, Ala-Opas M, Kosma VM. Prognostic value of CD44 standard, variant isoforms 3 and 6 and -catenin expression in local prostate cancer treated by radical prostatectomy. Eur Urol. 2000;38(5):555–62.

    Article  CAS  PubMed  Google Scholar 

  296. Aaltomaa S, Lipponen P, Ala-Opas M, Kosma VM. Expression and prognostic value of CD44 standard and variant v3 and v6 isoforms in prostate cancer. Eur Urol. 2001;39(2):138–44.

    Article  CAS  PubMed  Google Scholar 

  297. Ekici S, Ayhan A, Kendi S, Ozen H. Determination of prognosis in patients with prostate cancer treated with radical prostatectomy: prognostic value of CD44v6 score. J Urol. 2002;167(5):2037–41.

    Article  PubMed  Google Scholar 

  298. Tei H, Miyake H, Harada K, Fujisawa M. Expression profile of CD44s, CD44v6, and CD44v10 in localized prostate cancer: effect on prognostic outcomes following radical prostatectomy. Urol Oncol. 2014;32(5):694–700.

    Article  CAS  PubMed  Google Scholar 

  299. Ni J, Cozzi PJ, Hao JL, Beretov J, Chang L, Duan W, Shigdar S, Delprado WJ, Graham PH, Bucci J, Kearsley JH, Li Y. CD44 variant 6 is associated with prostate cancer metastasis and chemo-/radioresistance. Prostate. 2014;74(6):602–17.

    Article  CAS  PubMed  Google Scholar 

  300. Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, Elco CP, Lee N, Juneja VR, Zhan Q, Lian CG, Thomi R, Hoetzenecker W, Cozzio A, Dummer R, Mihm MC Jr, Flaherty KT, Frank MH, Murphy GF, Sharpe AH, Kupper TS, Schatton T. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell. 2015;162(6):1242–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen QY, Gindin M, Gubin MM, van der Windt GJW, Tonc E, Schreiber RD, Pearce EJ, Pearce EL. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162(6):1229–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Tuxhorn JA, Ayala GE, Rowley DR. Reactive stroma in prostate cancer progression. J Urol. 2001;166(6):2472–83.

    Article  CAS  PubMed  Google Scholar 

  303. Marcucci F, Bellone M, Caserta CA, Corti A. Pushing tumor cells towards a malignant phenotype: stimuli from the microenvironment, intercellular communications and alternative roads. Int J Cancer. 2014;135(6):1265–76.

    Article  CAS  PubMed  Google Scholar 

  304. Piali L, Fichtel A, Terpe HJ, Imhof BA, Gisler RH. Endothelial vascular cell adhesion molecule 1 expression is suppressed by melanoma and carcinoma. J Exp Med. 1995;181(2):811–6.

    Article  CAS  PubMed  Google Scholar 

  305. Bellone M, Mondino A, Corti A. Vascular targeting, chemotherapy and active immunotherapy: teaming up to attack cancer. Trends Immunol. 2008;29(5):235–41.

    Article  CAS  PubMed  Google Scholar 

  306. Pasqualini R, Koivunen E, Kain R, Lahdenranta J, Sakamoto M, Stryhn A, Ashmun RA, Shapiro LH, Arap W, Ruoslahti E. Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res. 2000;60(3):722–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  307. Curnis F, Arrigoni G, Sacchi A, Fischetti L, Arap W, Pasqualini R, Corti A. Differential binding of drugs containing the NGR motif to CD13 isoforms in tumor vessels, epithelia, and myeloid cells. Cancer Res. 2002;62(3):867–74.

    CAS  PubMed  Google Scholar 

  308. Curnis F, Sacchi A, Borgna L, Magni F, Gasparri A, Corti A. Enhancement of tumor necrosis factor alpha antitumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13). Nat Biotechnol. 2000;18(11):1185–90.

    Article  CAS  PubMed  Google Scholar 

  309. Curnis F, Sacchi A, Corti A. Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. J Clin Invest. 2002;110(4):475–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  310. Bertilaccio MT, Grioni M, Sutherland BW, Degl’Innocenti E, Freschi M, Jachetti E, Greenberg NM, Corti A, Bellone M. Vasculature-targeted tumor necrosis factor-alpha increases the therapeutic index of doxorubicin against prostate cancer. Prostate. 2008;68(10):1105–15.

    Article  CAS  PubMed  Google Scholar 

  311. Marcucci F, Bellone M, Rumio C, Corti A. Approaches to improve tumor accumulation and interactions between monoclonal antibodies and immune cells. MAbs. 2013;5(1):34–46.

    Article  PubMed  PubMed Central  Google Scholar 

  312. Calcinotto A, Grioni M, Jachetti E, Curnis F, Mondino A, Parmiani G, Corti A, Bellone M. Targeting TNF-alpha to neoangiogenic vessels enhances lymphocyte infiltration in tumors and increases the therapeutic potential of immunotherapy. J Immunol. 2012;188(6):2687–94.

    Article  CAS  PubMed  Google Scholar 

  313. Manzo T, Sturmheit T, Basso V, Petrozziello E, Hess Michelini R, Riba M, Freschi M, Elia AR, Grioni M, Curnis F, Protti MP, Schumacher TN, Debets R, Swartz MA, Corti A, Bellone M, Mondino A. T Cells redirected to a minor histocompatibility antigen instruct intratumoral TNFalpha expression and empower adoptive cell therapy for solid tumors. Cancer Res. 2017; 77(3):658–71.

    Article  PubMed  CAS  Google Scholar 

  314. Bellone M, Calcinotto A, Corti A. Won’t you come on in? How to favor lymphocyte infiltration in tumors. Oncoimmunology. 2012;1(6):986–8.

    Article  PubMed  PubMed Central  Google Scholar 

  315. Dondossola E, Gasparri AM, Colombo B, Sacchi A, Curnis F, Corti A. Chromogranin A restricts drug penetration and limits the ability of NGR-TNF to enhance chemotherapeutic efficacy. Cancer Res. 2011;71(17):5881–90.

    Article  CAS  PubMed  Google Scholar 

  316. van Laarhoven HW, Gambarota G, Heerschap A, Lok J, Verhagen I, Corti A, Toma S, Gallo Stampino C, van der Kogel A, Punt CJ. Effects of the tumor vasculature targeting agent NGR-TNF on the tumor microenvironment in murine lymphomas. Invest New Drugs. 2006;24(1):27–36.

    Article  CAS  PubMed  Google Scholar 

  317. Bellone M, Calcinotto A. Ways to enhance lymphocyte trafficking into tumors and fitness of tumor infiltrating lymphocytes. Front Oncol. 2013;3:231.

    Article  PubMed  PubMed Central  Google Scholar 

  318. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95.

    Article  CAS  PubMed  Google Scholar 

  319. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428–35.

    Article  CAS  PubMed  Google Scholar 

  320. Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, Cova A, Canese R, Jachetti E, Rossetti M, Huber V, Parmiani G, Generoso L, Santinami M, Borghi M, Fais S, Bellone M, Rivoltini L. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 2012;72(11):2746–56.

    Article  CAS  PubMed  Google Scholar 

  321. Grundstrom S, Dohlsten M, Sundstedt A. IL-2 unresponsiveness in anergic CD4(+) T cells is due to defective signaling through the common gamma-chain of the IL-2 receptor. J Immunol. 2000;164(3):1175–84.

    Article  CAS  PubMed  Google Scholar 

  322. Wells AD, Walsh MC, Sankaran D, Turka LA. T cell effector function and anergy avoidance are quantitatively linked to cell division. J Immunol. 2000;165(5):2432–43.

    Article  CAS  PubMed  Google Scholar 

  323. Bellone M, Calcinotto A, Filipazzi P, De Milito A, Fais S, Rivoltini L. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. Oncoimmunology. 2013;2(1):e22058.

    Article  PubMed  PubMed Central  Google Scholar 

  324. Zou WP. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer. 2005;5(4):263–74.

    Article  CAS  PubMed  Google Scholar 

  325. Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  326. Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M, Klebanoff CA, Eil RL, Hickman HD, Yu Z, Pan JH, Palmer DC, Phan AT, Goulding J, Gattinoni L, Goldrath AW, Belkaid Y, Restifo NP. Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell. 2016;166(5):1117–31 e1114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  327. Eil R, Vodnala SK, Clever D, Klebanoff CA, Sukumar M, Pan JH, Palmer DC, Gros A, Yamamoto TN, Patel SJ, Guittard GC, Yu ZY, Carbonaro V, Okkenhaug K, Schrump DS, Linehan WM, Roychoudhuri R, Restifo NP. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature. 2016;537(7621):539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  328. Shiba M, Suzuki H, Fujimoto M, Shimojo N, Imanaka-Yoshida K, Yoshida T, Kanamaru K, Matsushima S, Taki W. Imatinib mesylate prevents cerebral vasospasm after subarachnoid hemorrhage via inhibiting tenascin-C expression in rats. Neurobiol Dis. 2012;46(1):172–9.

    Article  CAS  PubMed  Google Scholar 

  329. Gorczynski RM, Chen Z, Shivagnahnam S, Taseva A, Wong K, Yu K, Khatri I. Potent immunosuppression by a bivalent molecule binding to CD200R and TGF-betaR. Transplantation. 2010;90(2):150–9.

    Article  PubMed  Google Scholar 

  330. Tsianakas A, Luger TA. The anti-IL-4 receptor alpha antibody dupilumab: facing a new era in treating atopic dermatitis. Expert Opin Biol Ther. 2015;15(11):1657–60.

    Article  CAS  PubMed  Google Scholar 

  331. Perez-Gomez MV, Sanchez-Nino MD, Sanz AB, Zheng B, Martin-Cleary C, Ruiz-Ortega M, Ortiz A, Fernandez-Fernandez B. Targeting inflammation in diabetic kidney disease: early clinical trials. Expert Opin Investig Drugs. 2016;25(9):1045–58.

    Article  CAS  PubMed  Google Scholar 

  332. Herlin T. Tocilizumab for the treatment of systemic juvenile idiopathic arthritis. Expert Rev Clin Immunol. 2012;8(6):517–25.

    Article  CAS  PubMed  Google Scholar 

  333. Munn DH, Bronte V. Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol. 2016;39:1–6.

    Article  CAS  PubMed  Google Scholar 

  334. Fukumura D, Kashiwagi S, Jain RK. The role of nitric oxide in tumour progression. Nat Rev Cancer. 2006;6(7):521–34.

    Article  CAS  PubMed  Google Scholar 

  335. Das A, Durrant D, Mitchell C, Mayton E, Hoke NN, Salloum FN, Park MA, Qureshi I, Lee R, Dent P, Kukreja RC. Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction. Proc Natl Acad Sci U S A. 2010;107(42):18202–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  336. Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C, Schultz PG, Reddy VA. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci U S A. 2009;106(1):268–73.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC; grant no. IG16807 to M. Bellone). Sara Caputo was awarded a fellowship from AIRC/FIRC and conducted this study in partial fulfillment of her Ph.D. at Università Vita-Salute San Raffaele. The authors apologize to all the investigators whose research has not been appropriately cited because of space constraints.

Conflicts of Interest

No potential conflicts of interest were disclosed.

Author information

Authors and Affiliations

  1. Cellular Immunology Unit, Department of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, DIBIT 1, Milan, Italy

    Matteo Bellone

  2. San Raffaele Scientific Institute, Milan, Italy

    Sara Caputo

  3. Università Vita-Salute San Raffaele, Milan, Italy

    Sara Caputo

Authors
  1. Matteo Bellone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sara Caputo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matteo Bellone .

Editor information

Editors and Affiliations

  1. Research Department, Sidra Medicine, Doha, Qatar

    Cristina Maccalli

  2. Department of DIBIMIS, University of Palermo, Laboratory of Cellular and Molecular Pathophysiology, Palermo, Italy

    Matilde Todaro

  3. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Soldano Ferrone

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Bellone, M., Caputo, S. (2019). Crosstalk Between Prostate Cancer Stem Cells and Immune Cells: Implications for Tumor Progression and Resistance to Immunotherapy. In: Maccalli, C., Todaro, M., Ferrone, S. (eds) Cancer Stem Cell Resistance to Targeted Therapy. Resistance to Targeted Anti-Cancer Therapeutics, vol 19. Springer, Cham. https://doi.org/10.1007/978-3-030-16624-3_8

Download citation

Publish with us

Policies and ethics

Search

Navigation