Tumor Immuno-Environment in Cancer Progression and Therapy

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1036)


The approvals of Provenge (Sipuleucel-T), Ipilimumab (Yervoy/anti-CTLA-4) and blockers of the PD-1 - PD-L1/PD-L2 pathway, such as nivolumab (Opdivo), pembrolizumab (Keytruda), or atezolizumab (Tecentriq), have established immunotherapy as a key component of comprehensive cancer care. Further, murine mechanistic studies and studies in immunocompromised patients have documented the critical role of immunity in effectiveness of radio- and chemotherapy. However, in addition to the ability of the immune system to control cancer progression, it can also promote tumor growth, via regulatory T cells (Tregs), myeloid-derived dendritic cells (MDSCs) and tumor associated macrophages (TAM), which can enhance survival of cancer cells directly or via the regulation of the tumor stroma.

An increasing body of evidence supports a central role for the tumor microenvironment (TME) and the interactions between tumor stroma, infiltrating immune cells and cancer cells during the induction and effector phase of anti-cancer immunity, and the overall effectiveness of immunotherapy and other forms of cancer treatment. In this chapter, we discuss the roles of key TME components during tumor progression, metastatic process and cancer therapy-induced tumor regression, as well as opportunities for their modulation to enhance the overall therapeutic benefit.


Tumor Microenvironment Cancer Immunotherapy Vaccines Checkpoint Blockade Adoptive Cell Therapies 


  1. 1.
    Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol. 2017;14(6):365–79.PubMedCrossRefGoogle Scholar
  2. 2.
    Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell. 2015;28(6):690–714.PubMedCrossRefGoogle Scholar
  3. 3.
    Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol. 2015;1(9):1325–32.PubMedCrossRefGoogle Scholar
  4. 4.
    Barker HE, Paget JT, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer. 2015;15(7):409–25.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Weber JS. Current perspectives on immunotherapy. Semin Oncol. 2014;41(Suppl 5):S14–29.PubMedCrossRefGoogle Scholar
  6. 6.
    Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501(7467):346–54.PubMedCrossRefGoogle Scholar
  9. 9.
    Gadducci A, Guerrieri ME, Greco C. Tissue biomarkers as prognostic variables of cervical cancer. Crit Rev Oncol Hematol. 2013;86(2):104–29.PubMedCrossRefGoogle Scholar
  10. 10.
    Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.PubMedCrossRefGoogle Scholar
  12. 12.
    Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Coley WB. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med. 1910;3(Surg Sect):1–48.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Nauts HC, Swift WE, Coley BL. The treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, reviewed in the light of modern research. Cancer Res. 1946;6(4):205–16.PubMedGoogle Scholar
  15. 15.
    Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10(9):909–15.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Astsaturov I, Petrella T, Bagriacik EU, et al. Amplification of virus-induced antimelanoma T-cell reactivity by high-dose interferon-alpha2b: implications for cancer vaccines. Clin Cancer Res. 2003;9(12):4347–55.PubMedGoogle Scholar
  17. 17.
    Rosenberg SA, Sherry RM, Morton KE, et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. J Immunol. 2005;175(9):6169–76.PubMedCrossRefGoogle Scholar
  18. 18.
    Bassi P. BCG (Bacillus of Calmette Guerin) therapy of high-risk superficial bladder cancer. Surg Oncol. 2002;11(1–2):77–83.PubMedCrossRefGoogle Scholar
  19. 19.
    Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S. Immunotherapy of cancer in 2012. CA Cancer J Clin. 2012;62(5):309–35.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5(1):43–51.PubMedCrossRefGoogle Scholar
  21. 21.
    Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kroemer G, Galluzzi L, Zitvogel L, Fridman WH. Colorectal cancer: the first neoplasia found to be under immunosurveillance and the last one to respond to immunotherapy? Oncoimmunology. 2015;4(7):e1058597.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064–74.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16(9):582–98.PubMedCrossRefGoogle Scholar
  25. 25.
    Harper J, Sainson RC. Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin Cancer Biol. 2014;25:69–77.PubMedCrossRefGoogle Scholar
  26. 26.
    Hill RP. The changing paradigm of tumour response to irradiation. Br J Radiol. 2017;90(1069):20160474.PubMedCrossRefGoogle Scholar
  27. 27.
    Sato T, Terai M, Tamura Y, Alexeev V, Mastrangelo MJ, Selvan SR. Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol Res. 2011;51(2–3):170–82.PubMedCrossRefGoogle Scholar
  28. 28.
    Sarvaria A, Madrigal JA, Saudemont A. B cell regulation in cancer and anti-tumor immunity. Cell Mol Immunol. 2017;14(8):662–74.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res. 2006;12(18):5423–34.PubMedCrossRefGoogle Scholar
  30. 30.
    Karasar P, Esendagli G. T helper responses are maintained by basal-like breast cancer cells and confer to immune modulation via upregulation of PD-1 ligands. Breast Cancer Res Treat. 2014;145(3):605–14.PubMedCrossRefGoogle Scholar
  31. 31.
    Wang C, Hillsamer P, Kim CH. Phenotype, effector function, and tissue localization of PD-1-expressing human follicular helper T cell subsets. BMC Immunol. 2011;12:53.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol. 2016;17(9):1025–36.PubMedCrossRefGoogle Scholar
  33. 33.
    Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L. Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol. 2012;12(4):239–52.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Whiteside TL, Herberman RB. The role of natural killer cells in immune surveillance of cancer. Curr Opin Immunol. 1995;7(5):704–10.PubMedCrossRefGoogle Scholar
  35. 35.
    Kroeger DR, Milne K, Nelson BH. Tumor-infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T-cell responses, and superior prognosis in ovarian cancer. Clin Cancer Res. 2016;22(12):3005–15.PubMedCrossRefGoogle Scholar
  36. 36.
    Joshi NS, Akama-Garren EH, Lu Y, et al. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity. 2015;43(3):579–90.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Goc J, Germain C, Vo-Bourgais TK, et al. Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Cancer Res. 2014;74(3):705–15.PubMedCrossRefGoogle Scholar
  38. 38.
    Kim KH, Kim TM, Go H, et al. Clinical significance of tumor-infiltrating FOXP3+ T cells in patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma. Cancer Sci. 2011;102(11):1972–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Alam I, Frahad K, Griffiths PA, Hurley M. Simultaneous gastrointestinal stromal tumor and mucosa-associated lymphoid tissue lymphoma of the stomach. J Clin Oncol. 2007;25(9):1136–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Schrama D, thor Straten P, Fischer WH, et al. Targeting of lymphotoxin-alpha to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity. 2001;14(2):111–21.PubMedCrossRefGoogle Scholar
  41. 41.
    Recamier JC. Recherches sur la Traitment du Cancer sur la Compression Methodique Simple ou Combinee et sure l'Histoire Generale de la Meme Maladie, vol. 21829. Paris: Gabon; 1829.Google Scholar
  42. 42.
    Price JE, Aukerman SL, Fidler IJ. Evidence that the process of murine melanoma metastasis is sequential and selective and contains stochastic elements. Cancer Res. 1986;46(10):5172–8.PubMedGoogle Scholar
  43. 43.
    Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124(2):263–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature. 1980;284(5751):67–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Bauvois B. New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. Biochim Biophys Acta. 2012;1825(1):29–36.PubMedGoogle Scholar
  46. 46.
    Rosenbaum E, Zahurak M, Sinibaldi V, et al. Marimastat in the treatment of patients with biochemically relapsed prostate cancer: a prospective randomized, double-blind, phase I/II trial. Clin Cancer Res. 2005;11(12):4437–43.PubMedCrossRefGoogle Scholar
  47. 47.
    Overall CM, Kleifeld O. Tumour microenvironment—opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006;6(3):227–39.PubMedCrossRefGoogle Scholar
  48. 48.
    Gross S, Marymont JH Jr. Extramedullary hematopoiesis and metastatic cancer in the spleen. Am J Clin Pathol. 1963;40:194–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Eccles SA, Alexander P. Macrophage content of tumours in relation to metastatic spread and host immune reaction. Nature. 1974;250(5468):667–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86.PubMedCrossRefGoogle Scholar
  51. 51.
    Mantovani A, Sica A, Locati M. New vistas on macrophage differentiation and activation. Eur J Immunol. 2007;37(1):14–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64.PubMedCrossRefGoogle Scholar
  53. 53.
    Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity. 2005;23(4):344–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Goerdt S, Orfanos CE. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity. 1999;10(2):137–42.PubMedCrossRefGoogle Scholar
  55. 55.
    Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35.PubMedCrossRefGoogle Scholar
  56. 56.
    Anderson CF, Mosser DM. A novel phenotype for an activated macrophage: the type 2 activated macrophage. J Leukoc Biol. 2002;72(1):101–6.PubMedGoogle Scholar
  57. 57.
    Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009;86(5):1065–73.PubMedCrossRefGoogle Scholar
  58. 58.
    Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol. 2012;188(1):21–8.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44.PubMedCrossRefGoogle Scholar
  60. 60.
    Sinha P, Clements VK, Ostrand-Rosenberg S. Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res. 2005;65(24):11743–51.PubMedCrossRefGoogle Scholar
  61. 61.
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549–55.PubMedCrossRefGoogle Scholar
  62. 62.
    Elgert KD, Alleva DG, Mullins DW. Tumor-induced immune dysfunction: the macrophage connection. J Leukoc Biol. 1998;64(3):275–90.PubMedGoogle Scholar
  63. 63.
    Lin EY, Nguyen AV, Russell RG, Pollard JW. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 2001;193(6):727–40.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2008;9(4):239–52.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Hamada I, Kato M, Yamasaki T, et al. Clinical effects of tumor-associated macrophages and dendritic cells on renal cell carcinoma. Anticancer Res. 2002;22(6C):4281–4.PubMedGoogle Scholar
  66. 66.
    Lewis C, Murdoch C. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol. 2005;167(3):627–35.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Talmadge JE, Key M, Fidler IJ. Macrophage content of metastatic and nonmetastatic rodent neoplasms. J Immunol. 1981;126(6):2245–8.PubMedGoogle Scholar
  68. 68.
    Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362(10):875–85.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Key M, Talmadge JE, Fidler IJ. Lack of correlation between the progressive growth of spontaneous metastases and their content of infiltrating macrophages. J Reticuloendothel Soc. 1982;32(5):387–96.PubMedGoogle Scholar
  70. 70.
    Evans R, Lawler EM. Macrophage content and immunogenicity of C57BL/6J and BALB/cByJ methylcholanthrene-induced sarcomas. Int J Cancer. 1980;26(6):831–5.PubMedCrossRefGoogle Scholar
  71. 71.
    Steele RJ, Eremin O, Brown M, Hawkins RA. A high macrophage content in human breast cancer is not associated with favourable prognostic factors. Br J Surg. 1984;71(6):456–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Robinson BD, Sica GL, Liu YF, et al. Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res. 2009;15(7):2433–41.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4(1):71–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Qian B-Z, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39–51.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Kang JC, Chen JS, Lee CH, Chang JJ, Shieh YS. Intratumoral macrophage counts correlate with tumor progression in colorectal cancer. J Surg Oncol. 2010;102(3):242–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Sun XF, Zhang H. Clinicopathological significance of stromal variables: angiogenesis, lymphangiogenesis, inflammatory infiltration, MMP and PINCH in colorectal carcinomas. Mol Cancer. 2006;5:43.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Chen JJ, Lin YC, Yao PL, et al. Tumor-associated macrophages: the double-edged sword in cancer progression. J Clin Oncol. 2005;23(5):953–64.PubMedCrossRefGoogle Scholar
  78. 78.
    Ryder M, Ghossein RA, Ricarte-Filho JC, Knauf JA, Fagin JA. Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr Relat Cancer. 2008;15(4):1069–74.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Zhu XD, Zhang JB, Zhuang PY, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008;26(16):2707–16.PubMedCrossRefGoogle Scholar
  80. 80.
    Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196(3):254–65.PubMedCrossRefGoogle Scholar
  81. 81.
    Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.PubMedCrossRefGoogle Scholar
  82. 82.
    Bronte V, Wang M, Overwijk WW, et al. Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. J Immunol. 1998;161(10):5313–20.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Kusmartsev S, Gabrilovich DI. STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol. 2005;174(8):4880–91.PubMedCrossRefGoogle Scholar
  84. 84.
    Kalinski P. Dendritic cells in immunotherapy of established cancer: roles of signals 1, 2, 3 and 4. Curr Opin Investig Drugs. 2009;10(6):526–35.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Obermajer N, Kalinski P. Key role of the positive feedback between PGE(2) and COX2 in the biology of myeloid-derived suppressor cells. Oncoimmunology. 2012;1(5):762–4.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood. 2011;118(20):5498–505.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Obermajer N, Muthuswamy R, Odunsi K, Edwards RP, Kalinski P. PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. 2011;71(24):7463–70.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162–74.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Young MR, Lathers DM. Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. Int J Immunopharmacol. 1999;21(4):241–52.PubMedCrossRefGoogle Scholar
  90. 90.
    Vasconcelos ZF, Dos Santos BM, Farache J, et al. G-CSF-treated granulocytes inhibit acute graft-versus-host disease. Blood. 2006;107(5):2192–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Ohm JE, Carbone DP. VEGF as a mediator of tumor-associated immunodeficiency. Immunol Res. 2001;23(2–3):263–72.PubMedCrossRefGoogle Scholar
  92. 92.
    Ellis LM, Takahashi Y, Liu W, Shaheen RM. Vascular endothelial growth factor in human colon cancer: biology and therapeutic implications. Oncologist. 2000;5(Suppl 1):11–5.PubMedCrossRefGoogle Scholar
  93. 93.
    Toi M, Kondo S, Suzuki H, et al. Quantitative analysis of vascular endothelial growth factor in primary breast cancer. Cancer. 1996;77(6):1101–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996;2(10):1096–103.PubMedCrossRefGoogle Scholar
  95. 95.
    Saito H, Tsujitani S, Ikeguchi M, Maeta M, Kaibara N. Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. Br J Cancer. 1998;78(12):1573–7.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Rodriguez PC, Ernstoff MS, Hernandez C, et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 2009;69(4):1553–60.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Almand B, Clark JI, Nikitina E, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001;166(1):678–89.PubMedCrossRefGoogle Scholar
  98. 98.
    Filipazzi P, Valenti R, Huber V, et al. Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol. 2007;25(18):2546–53.PubMedCrossRefGoogle Scholar
  99. 99.
    Arina A, Bronte V. Myeloid-derived suppressor cell impact on endogenous and adoptively transferred T cells. Curr Opin Immunol. 2015;33:120–5.PubMedCrossRefGoogle Scholar
  100. 100.
    Allavena P, Mantovani A. Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol. 2012;167(2):195–205.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest. 2015;125(9):3356–64.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Nagaraj S, Gabrilovich DI. Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res. 2008;68(8):2561–3.PubMedCrossRefGoogle Scholar
  103. 103.
    Nagaraj S, Gabrilovich DI. Myeloid-derived suppressor cells in human cancer. Cancer J. 2010;16(4):348–53.PubMedCrossRefGoogle Scholar
  104. 104.
    Dieu-Nosjean MC, Antoine M, Danel C, et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol. 2008;26(27):4410–7.PubMedCrossRefGoogle Scholar
  105. 105.
    Elliott B, Scolyer RA, Suciu S, et al. Long-term protective effect of mature DC-LAMP+ dendritic cell accumulation in sentinel lymph nodes containing micrometastatic melanoma. Clin Cancer Res. 2007;13(13):3825–30.PubMedCrossRefGoogle Scholar
  106. 106.
    Gallo O, Bianchi S, Giannini A, Gallina E, Libonati GA, Fini-Storchi O. Correlations between histopathological and biological findings in nasopharyngeal carcinoma and its prognostic significance. Laryngoscope. 1991;101(5):487–93.PubMedCrossRefGoogle Scholar
  107. 107.
    Giannini A, Bianchi S, Messerini L, et al. Prognostic significance of accessory cells and lymphocytes in nasopharyngeal carcinoma. Pathol Res Pract. 1991;187(4):496–502.PubMedCrossRefGoogle Scholar
  108. 108.
    Kashimura S, Saze Z, Terashima M, et al. CD83(+) dendritic cells and Foxp3(+) regulatory T cells in primary lesions and regional lymph nodes are inversely correlated with prognosis of gastric cancer. Gastric Cancer. 2012;15(2):144–53.PubMedCrossRefGoogle Scholar
  109. 109.
    Kobayashi M, Suzuki K, Yashi M, Yuzawa M, Takayashiki N, Morita T. Tumor infiltrating dendritic cells predict treatment response to immmunotherapy in patients with metastatic renal cell carcinoma. Anticancer Res. 2007;27(2):1137–41.PubMedGoogle Scholar
  110. 110.
    Mansuet-Lupo A, Alifano M, Pecuchet N, et al. Intratumoral immune cell densities are associated with lung adenocarcinoma gene alterations. Am J Respir Crit Care Med. 2016;194(11):1403–12.PubMedCrossRefGoogle Scholar
  111. 111.
    Reichert TE, Scheuer C, Day R, Wagner W, Whiteside TL. The number of intratumoral dendritic cells and zeta-chain expression in T cells as prognostic and survival biomarkers in patients with oral carcinoma. Cancer. 2001;91(11):2136–47.PubMedCrossRefGoogle Scholar
  112. 112.
    Tsukayama S, Omura K, Yoshida K, Tanaka Y, Watanabe G. Prognostic value of CD83-positive mature dendritic cells and their relation to vascular endothelial growth factor in advanced human gastric cancer. Oncol Rep. 2005;14(2):369–75.PubMedGoogle Scholar
  113. 113.
    Zeid NA, Muller HK. S100 positive dendritic cells in human lung tumors associated with cell differentiation and enhanced survival. Pathology. 1993;25(4):338–43.PubMedCrossRefGoogle Scholar
  114. 114.
    Kalinski P, Muthuswamy R, Urban J. Dendritic cells in cancer immunotherapy: vaccines and combination immunotherapies. Expert Rev Vaccines. 2013;12(3):285–95.PubMedCrossRefGoogle Scholar
  115. 115.
    Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014;15(7):e257–67.PubMedCrossRefGoogle Scholar
  116. 116.
    Czerniecki BJ, Roses RE, Koski GK. Development of vaccines for high-risk ductal carcinoma in situ of the breast. Cancer Res. 2007;67(14):6531–4.PubMedCrossRefGoogle Scholar
  117. 117.
    Fong L, Engleman EG. Dendritic cells in cancer immunotherapy. Annu Rev Immunol. 2000;18:245–73.PubMedCrossRefGoogle Scholar
  118. 118.
    Gilboa E. DC-based cancer vaccines. J Clin Invest. 2007;117(5):1195–203.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Kirkwood JM, Tarhini AA, Panelli MC, et al. Next generation of immunotherapy for melanoma. J Clin Oncol. 2008;26(20):3445–55.PubMedCrossRefGoogle Scholar
  120. 120.
    Simons JW. Prostate cancer immunotherapy: beyond immunity to curability. Cancer Immunol Res. 2014;2(11):1034–43.PubMedCrossRefGoogle Scholar
  121. 121.
    Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–52.PubMedCrossRefGoogle Scholar
  122. 122.
    Andersen BM, Ohlfest JR. Increasing the efficacy of tumor cell vaccines by enhancing cross priming. Cancer Lett. 2012;325(2):155–64.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    de Vries IJ, Lesterhuis WJ, Scharenborg NM, et al. Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. Clin Cancer Res. 2003;9(14):5091–100.PubMedGoogle Scholar
  124. 124.
    Adema GJ, de Vries IJ, Punt CJ, Figdor CG. Migration of dendritic cell based cancer vaccines: in vivo veritas? Curr Opin Immunol. 2005;17(2):170–4.PubMedCrossRefGoogle Scholar
  125. 125.
    Kalinski P, Hilkens CM, Wierenga EA, Kapsenberg ML. T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal. Immunol Today. 1999;20(12):561–7.PubMedCrossRefGoogle Scholar
  126. 126.
    Kunz M, Toksoy A, Goebeler M, Engelhardt E, Brocker E, Gillitzer R. Strong expression of the lymphoattractant C-X-C chemokine Mig is associated with heavy infiltration of T cells in human malignant melanoma. J Pathol. 1999;189(4):552–8.PubMedCrossRefGoogle Scholar
  127. 127.
    Calzascia T, Masson F, Di Berardino-Besson W, et al. Homing phenotypes of tumor-specific CD8 T cells are predetermined at the tumor site by crosspresenting APCs. Immunity. 2005;22(2):175–84.PubMedCrossRefGoogle Scholar
  128. 128.
    Almand B, Resser JR, Lindman B, et al. Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res. 2000;6(5):1755–66.PubMedGoogle Scholar
  129. 129.
    Della Bella S, Gennaro M, Vaccari M, et al. Altered maturation of peripheral blood dendritic cells in patients with breast cancer. Br J Cancer. 2003;89(8):1463–72.PubMedCrossRefGoogle Scholar
  130. 130.
    Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12(4):265–77.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Pinzon-Charry A, Maxwell T, Lopez JA. Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol. 2005;83(5):451–61.PubMedCrossRefGoogle Scholar
  132. 132.
    Wen H, Schaller MA, Dou Y, Hogaboam CM, Kunkel SL. Dendritic cells at the interface of innate and acquired immunity: the role for epigenetic changes. J Leukoc Biol. 2008;83(3):439–46.PubMedCrossRefGoogle Scholar
  133. 133.
    Melief CJ. Cancer immunotherapy by dendritic cells. Immunity. 2008;29(3):372–83.PubMedCrossRefGoogle Scholar
  134. 134.
    Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267–96.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Uchida K, Schneider S, Yochim JM, et al. Intratumoral COX-2 gene expression is a predictive factor for colorectal cancer response to fluoropyrimidine-based chemotherapy. Clin Cancer Res. 2005;11(9):3363–8.PubMedCrossRefGoogle Scholar
  136. 136.
    Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.PubMedCrossRefGoogle Scholar
  137. 137.
    Galon J, Fridman WH, Pages F. The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res. 2007;67(5):1883–6.PubMedCrossRefGoogle Scholar
  138. 138.
    Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3):203–13.PubMedCrossRefGoogle Scholar
  139. 139.
    Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102(51):18538–43.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G. Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res. 2011;71(17):5601–5.PubMedCrossRefGoogle Scholar
  141. 141.
    Formica V, Cereda V, di Bari MG, et al. Peripheral CD45RO, PD-1, and TLR4 expression in metastatic colorectal cancer patients treated with bevacizumab, fluorouracil, and irinotecan (FOLFIRI-B). Med Oncol. 2013;30(4):743.PubMedCrossRefGoogle Scholar
  142. 142.
    Yamada N, Oizumi S, Kikuchi E, et al. CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother. 2010;59(10):1543–9.PubMedCrossRefGoogle Scholar
  143. 143.
    Anraku M, Cunningham KS, Yun Z, et al. Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2008;135(4):823–9.PubMedCrossRefGoogle Scholar
  144. 144.
    Pages F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353(25):2654–66.PubMedCrossRefGoogle Scholar
  145. 145.
    Naito Y, Saito K, Shiiba K, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58(16):3491–4.PubMedGoogle Scholar
  146. 146.
    Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–9.PubMedCrossRefGoogle Scholar
  147. 147.
    Chaput N, Louafi S, Bardier A, et al. Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue. Gut. 2009;58(4):520–9.PubMedCrossRefGoogle Scholar
  148. 148.
    Clarke SL, Betts GJ, Plant A, et al. CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS One. 2006;1:e129.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Michel S, Benner A, Tariverdian M, et al. High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. Br J Cancer. 2008;99(11):1867–73.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Brigati C, Noonan DM, Albini A, Benelli R. Tumors and inflammatory infiltrates: friends or foes? Clin Exp Metastasis. 2002;19(3):247–58.PubMedCrossRefGoogle Scholar
  151. 151.
    Fu J, Xu D, Liu Z, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132(7):2328–39.PubMedCrossRefGoogle Scholar
  152. 152.
    Carreras J, Lopez-Guillermo A, Fox BC, et al. High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood. 2006;108(9):2957–64.PubMedCrossRefGoogle Scholar
  153. 153.
    Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. Haematologica. 2008;93(2):193–200.PubMedCrossRefGoogle Scholar
  154. 154.
    Pagès F, Galon J, Dieu-Nosjean MC, Tartour E, Sautès-Fridman C, Fridman WH. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene. 2009;29(8):1093–102.PubMedCrossRefGoogle Scholar
  155. 155.
    Siddiqui SA, Frigola X, Bonne-Annee S, et al. Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma. Clin Cancer Res. 2007;13(7):2075–81.PubMedCrossRefGoogle Scholar
  156. 156.
    Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol. 1999;17(3):976–83.PubMedCrossRefGoogle Scholar
  157. 157.
    Elder DE, Gimotty PA, Guerry D. Cutaneous melanoma: estimating survival and recurrence risk based on histopathologic features. Dermatol Ther. 2005;18(5):369–85.PubMedCrossRefGoogle Scholar
  158. 158.
    Badoual C, Hans S, Rodriguez J, et al. Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res. 2006;12(2):465–72.PubMedCrossRefGoogle Scholar
  159. 159.
    Bromwich EJ, McArdle PA, Canna K, et al. The relationship between T-lymphocyte infiltration, stage, tumour grade and survival in patients undergoing curative surgery for renal cell cancer. Br J Cancer. 2003;89(10):1906–8.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Hennequin A, Derangere V, Boidot R, et al. Tumor infiltration by Tbet+ effector T cells and CD20+ B cells is associated with survival in gastric cancer patients. Oncoimmunology. 2016;5(2):e1054598.PubMedCrossRefGoogle Scholar
  161. 161.
    Xu B, Chen L, Li J, et al. Prognostic value of tumor infiltrating NK cells and macrophages in stage II+III esophageal cancer patients. Oncotarget. 2016;7(46):74904–16.PubMedPubMedCentralGoogle Scholar
  162. 162.
    Donadon M, Hudspeth K, Cimino M, et al. Increased infiltration of natural killer and T cells in colorectal liver metastases improves patient overall survival. J Gastrointest Surg. 2017;21(8):1226–36.PubMedCrossRefGoogle Scholar
  163. 163.
    Introna M, Allavena P, Biondi A, Colombo N, Villa A, Mantovani A. Defective natural killer activity within human ovarian tumors: low numbers of morphologically defined effectors present in situ. J Natl Cancer Inst. 1983;70(1):21–6.PubMedGoogle Scholar
  164. 164.
    Li T, Zhang Q, Jiang Y, et al. Gastric cancer cells inhibit natural killer cell proliferation and induce apoptosis via prostaglandin E2. Oncoimmunology. 2016;5(2):e1069936.PubMedCrossRefGoogle Scholar
  165. 165.
    Sznurkowski JJ, Zawrocki A, Biernat W. Subtypes of cytotoxic lymphocytes and natural killer cells infiltrating cancer nests correlate with prognosis in patients with vulvar squamous cell carcinoma. Cancer Immunol Immunother. 2014;63(3):297–303.PubMedCrossRefGoogle Scholar
  166. 166.
    Granzin M, Wagner J, Kohl U, Cerwenka A, Huppert V, Ullrich E. Shaping of natural killer cell antitumor activity by ex vivo cultivation. Front Immunol. 2017;8:458.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Introna M, Mantovani A. Natural killer cells in human solid tumors. Cancer Metastasis Rev. 1983;2(4):337–50.PubMedCrossRefGoogle Scholar
  168. 168.
    Pross HF, Lotzova E. Role of natural killer cells in cancer. Nat Immun. 1993;12(4–5):279–92.PubMedGoogle Scholar
  169. 169.
    Tatsumi T, Takehara T. Impact of natural killer cells on chronic hepatitis C and hepatocellular carcinoma. Hepatol Res. 2016;46(5):416–22.PubMedCrossRefGoogle Scholar
  170. 170.
    Whiteside TL, Vujanovic NL, Herberman RB. Natural killer cells and tumor therapy. Curr Top Microbiol Immunol. 1998;230:221–44.PubMedGoogle Scholar
  171. 171.
    Yang Y, Cao JZ, Lan SM, et al. Association of improved locoregional control with prolonged survival in early-stage extranodal nasal-type natural killer/T-cell lymphoma. JAMA Oncol. 2017;3(1):83–91.PubMedCrossRefGoogle Scholar
  172. 172.
    Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med. 2002;195(3):343–51.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Piccioli D, Sbrana S, Melandri E, Valiante NM. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med. 2002;195(3):335–41.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med. 2002;195(3):327–33.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Mailliard RB, Son YI, Redlinger R, et al. Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function. J Immunol. 2003;171(5):2366–73.PubMedCrossRefGoogle Scholar
  176. 176.
    Kelly JM, Darcy PK, Markby JL, et al. Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection. Nat Immunol. 2002;3(1):83–90.PubMedCrossRefGoogle Scholar
  177. 177.
    Strbo N, Oizumi S, Sotosek-Tokmadzic V, Podack ER. Perforin is required for innate and adaptive immunity induced by heat shock protein gp96. Immunity. 2003;18(3):381–90.PubMedCrossRefGoogle Scholar
  178. 178.
    Mocikat R, Braumuller H, Gumy A, et al. Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity. 2003;19(4):561–9.PubMedCrossRefGoogle Scholar
  179. 179.
    Westwood JA, Kelly JM, Tanner JE, Kershaw MH, Smyth MJ, Hayakawa Y. Cutting edge: novel priming of tumor-specific immunity by NKG2D-triggered NK cell-mediated tumor rejection and Th1-independent CD4+ T cell pathway. J Immunol. 2004;172(2):757–61.PubMedCrossRefGoogle Scholar
  180. 180.
    Cudkowicz G, Hochman PS. Do natural killer cells engage in regulated reactions against self to ensure homeostasis? Immunol Rev. 1979;44:13–41.PubMedCrossRefGoogle Scholar
  181. 181.
    Tse BW, Collins A, Oehler MK, Zippelius A, Heinzelmann-Schwarz VA. Antibody-based immunotherapy for ovarian cancer: where are we at? Ann Oncol. 2014;25(2):322–31.PubMedCrossRefGoogle Scholar
  182. 182.
    Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33(34):4015–22.PubMedCrossRefGoogle Scholar
  183. 183.
    Speetjens FM, Zeestraten EC, Kuppen PJ, Melief CJ, van der Burg SH. Colorectal cancer vaccines in clinical trials. Expert Rev Vaccines. 2011;10(6):899–921.PubMedCrossRefGoogle Scholar
  184. 184.
    de Weger VA, Turksma AW, Voorham QJ, et al. Clinical effects of adjuvant active specific immunotherapy differ between patients with microsatellite-stable and microsatellite-instable colon cancer. Clin Cancer Res. 2012;18(3):882–9.PubMedCrossRefGoogle Scholar
  185. 185.
    Koido S, Ohkusa T, Homma S, et al. Immunotherapy for colorectal cancer. World J Gastroenterol. 2013;19(46):8531–42.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Ji RR, Chasalow SD, Wang L, et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother. 2012;61(7):1019–31.PubMedCrossRefGoogle Scholar
  187. 187.
    Gatalica Z, Snyder C, Maney T, et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomark Prev. 2014;23(12):2965–70.CrossRefGoogle Scholar
  188. 188.
    Phillips SM, Banerjea A, Feakins R, Li SR, Bustin SA, Dorudi S. Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br J Surg. 2004;91(4):469–75.PubMedCrossRefGoogle Scholar
  189. 189.
    Demaria O, De Gassart A, Coso S, et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc Natl Acad Sci U S A. 2015;112(50):15408–13.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Vasaturo A, Halilovic A, Bol KF, et al. T-cell landscape in a primary melanoma predicts the survival of patients with metastatic disease after their treatment with dendritic cell vaccines. Cancer Res. 2016;76(12):3496–506.PubMedCrossRefGoogle Scholar
  191. 191.
    Fong L, Carroll P, Weinberg V, et al. Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer. J Natl Cancer Inst. 2014;106(11):1–9.CrossRefGoogle Scholar
  192. 192.
    Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015;16(13):e498–509.PubMedCrossRefGoogle Scholar
  193. 193.
    Vanpouille-Box C, Pilones KA, Wennerberg E, Formenti SC, Demaria S. In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment. Vaccine. 2015;33(51):7415–22.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Nobler MP. The abscopal effect in malignant lymphoma and its relationship to lymphocyte circulation. Radiology. 1969;93(2):410–2.PubMedCrossRefGoogle Scholar
  195. 195.
    Gichangi P, Bwayo J, Estambale B, et al. HIV impact on acute morbidity and pelvic tumor control following radiotherapy for cervical cancer. Gynecol Oncol. 2006;100(2):405–11.PubMedCrossRefGoogle Scholar
  196. 196.
    Kotoula V, Chatzopoulos K, Lakis S, et al. Tumors with high-density tumor infiltrating lymphocytes constitute a favorable entity in breast cancer: a pooled analysis of four prospective adjuvant trials. Oncotarget. 2016;7(4):5074–87.PubMedCrossRefGoogle Scholar
  197. 197.
    Rao N, Qiu J, Wu J, et al. Significance of tumor-infiltrating lymphocytes and the expression of topoisomerase IIalpha in the prediction of the clinical outcome of patients with triple-negative breast cancer after taxane-anthracycline-based neoadjuvant chemotherapy. Chemotherapy. 2017;62(4):246–55.PubMedCrossRefGoogle Scholar
  198. 198.
    Wang K, Xu J, Zhang T, Xue D. Tumor-infiltrating lymphocytes in breast cancer predict the response to chemotherapy and survival outcome: a meta-analysis. Oncotarget. 2016;7(28):44288–98.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Andre F, Dieci MV, Dubsky P, et al. Molecular pathways: involvement of immune pathways in the therapeutic response and outcome in breast cancer. Clin Cancer Res. 2013;19(1):28–33.PubMedCrossRefGoogle Scholar
  200. 200.
    Vacchelli E, Semeraro M, Enot DP, et al. Negative prognostic impact of regulatory T cell infiltration in surgically resected esophageal cancer post-radiochemotherapy. Oncotarget. 2015;6(25):20840–50.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Frey B, Hehlgans S, Rodel F, Gaipl US. Modulation of inflammation by low and high doses of ionizing radiation: implications for benign and malign diseases. Cancer Lett. 2015;368(2):230–7.PubMedCrossRefGoogle Scholar
  202. 202.
    Martin D, Rodel F, Balermpas P, Rodel C, Fokas E. The immune microenvironment and HPV in anal cancer: rationale to complement chemoradiation with immunotherapy. Biochim Biophys Acta. 2017;1868(1):221–30.PubMedGoogle Scholar
  203. 203.
    Obeid M, Tesniere A, Ghiringhelli F, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13(1):54–61.PubMedCrossRefGoogle Scholar
  204. 204.
    Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13(9):1050–9.PubMedCrossRefGoogle Scholar
  205. 205.
    Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21(1):15–25.PubMedCrossRefGoogle Scholar
  206. 206.
    Musha H, Ohtani H, Mizoi T, et al. Selective infiltration of CCR5(+)CXCR3(+) T lymphocytes in human colorectal carcinoma. Int J Cancer. 2005;116(6):949–56.PubMedCrossRefGoogle Scholar
  207. 207.
    Ohtani H, Jin Z, Takegawa S, Nakayama T, Yoshie O. Abundant expression of CXCL9 (MIG) by stromal cells that include dendritic cells and accumulation of CXCR3+ T cells in lymphocyte-rich gastric carcinoma. J Pathol. 2009;217(1):21–31.PubMedCrossRefGoogle Scholar
  208. 208.
    Muthuswamy R, Berk E, Junecko BF, et al. NF-kappaB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells. Cancer Res. 2012;72(15):3735–43.PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Watchmaker PB, Berk E, Muthuswamy R, et al. Independent regulation of chemokine responsiveness and cytolytic function versus CD8+ T cell expansion by dendritic cells. J Immunol. 2010;184(2):591–7.PubMedCrossRefGoogle Scholar
  210. 210.
    Muthuswamy R, Urban J, Lee JJ, Reinhart TA, Bartlett D, Kalinski P. Ability of mature dendritic cells to interact with regulatory T cells is imprinted during maturation. Cancer Res. 2008;68(14):5972–8.PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Fujita M, Zhu X, Ueda R, et al. Effective immunotherapy against murine gliomas using type 1 polarizing dendritic cells—significant roles of CXCL10. Cancer Res. 2009;69(4):1587–95.PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Zhu X, Fallert-Junecko BA, Fujita M, et al. Poly-ICLC promotes the infiltration of effector T cells into intracranial gliomas via induction of CXCL10 in IFN-alpha and IFN-gamma dependent manners. Cancer Immunol Immunother. 2010;59(9):1401–9.PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Okada H. Brain tumor immunotherapy with type-1 polarizing strategies. Ann N Y Acad Sci. 2009;1174:18–23.PubMedCrossRefGoogle Scholar
  214. 214.
    Okada H, Kalinski P, Ueda R, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol. 2011;29(3):330–6.PubMedCrossRefGoogle Scholar
  215. 215.
    Muthuswamy R, Wang L, Pitteroff J, Gingrich JR, Kalinski P. Combination of IFNalpha and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction. J Immunother Cancer. 2015;3:6.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Muthuswamy R, Corman JM, Dahl K, Chatta GS, Kalinski P. Functional reprogramming of human prostate cancer to promote local attraction of effector CD8(+) T cells. Prostate. 2016;76(12):1095–105.PubMedCrossRefGoogle Scholar
  217. 217.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.PubMedCrossRefGoogle Scholar
  218. 218.
    Wong JL, Obermajer N, Odunsi K, Edwards RP, Kalinski P. Synergistic COX2 induction by IFNgamma and TNFalpha self-limits type-1 immunity in the human tumor microenvironment. Cancer Immunol Res. 2016;4(4):303–11.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Medicine and Center for ImmunotherapyRoswell Park Cancer InstituteBuffaloUSA
  2. 2.University of Nebraska Medical Center, 986495 Nebraska Medical CenterOmahaUSA

Personalised recommendations