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Systemic Correlates of the Tumor Microenvironment

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Tumor Microenvironment

Part of the book series: Cancer Treatment and Research ((CTAR,volume 180))

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Abstract

It is increasingly recognized that cancer does not involve only formation of a tumor, but also systemic changes in the host. Alterations in number, spatial relationship, and function of immune cells have been identified in cancer patients’ blood, lymph nodes, spleen, and bone marrow. Importantly, these changes correlate with clinical outcome, demonstrating that systemic effects may persist in some patients after initial therapy that underlie future relapse. In this chapter, we will review these recent findings on the systemic effects of cancer.

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References

  1. Blenman KRM, He TF, Frankel PH, Ruel NH, Schwartz EJ, Krag DN, Tan LK, Yim JH, Mortimer JE, Yuan Y et al (2018) Sentinel lymph node B cells can predict disease-free survival in breast cancer patients. NPJ Breast Cancer 4:28

    Article  PubMed  PubMed Central  Google Scholar 

  2. Borniger JC, Walker Ii WH, Surbhi, Emmer KM, Zhang N, Zalenski AA, Muscarella SL, Fitzgerald JA, Smith AN, Braam CJ et al (2018) A role for hypocretin/orexin in metabolic and sleep abnormalities in a mouse model of non-metastatic breast cancer. Cell Metab 28: 118–129.e115

    Google Scholar 

  3. Brewitz A, Eickhoff S, Dahling S, Quast T, Bedoui S, Kroczek RA, Kurts C, Garbi N, Barchet W, Iannacone M et al (2017) CD8(+) T cells orchestrate pDC-XCR1(+) dendritic cell spatial and functional cooperativity to optimize priming. Immunity 46:205–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bronte V, Pittet MJ (2013) The spleen in local and systemic regulation of immunity. Immunity 39:806–818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Casbon AJ, Reynaud D, Park C, Khuc E, Gan DD, Schepers K, Passegue E, Werb Z (2015) Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc Natl Acad Sci U S A 112:E566–E575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chang AY, Bhattacharya N, Mu J, Setiadi AF, Carcamo-Cavazos V, Lee GH, Simons DL, Yadegarynia S, Hemati K, Kapelner A et al (2013) Spatial organization of dendritic cells within tumor draining lymph nodes impacts clinical outcome in breast cancer patients. J Transl Med 11:242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cochran AJ, Huang RR, Lee J, Itakura E, Leong SP, Essner R (2006) Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol 6:659–670

    Article  CAS  PubMed  Google Scholar 

  8. Cortez-Retamozo V, Etzrodt M, Newton A, Rauch PJ, Chudnovskiy A, Berger C, Ryan RJ, Iwamoto Y, Marinelli B, Gorbatov R et al (2012) Origins of tumor-associated macrophages and neutrophils. Proc Natl Acad Sci U S A 109:2491–2496

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cortez-Retamozo V, Etzrodt M, Newton A, Ryan R, Pucci F, Sio SW, Kuswanto W, Rauch PJ, Chudnovskiy A, Iwamoto Y et al (2013) Angiotensin II drives the production of tumor-promoting macrophages. Immunity 38:296–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Critchley-Thorne RJ, Simons DL, Yan N, Miyahira AK, Dirbas FM, Johnson DL, Swetter SM, Carlson RW, Fisher GA, Koong A et al (2009) Impaired interferon signaling is a common immune defect in human cancer. Proc Natl Acad Sci U S A 106:9010–9015

    Article  PubMed  PubMed Central  Google Scholar 

  11. Critchley-Thorne RJ, Yan N, Nacu S, Weber J, Holmes SP, Lee PP (2007) Down-regulation of the interferon signaling pathway in T lymphocytes from patients with metastatic melanoma. PLoS Med 4:e176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cyster JG, Schwab SR (2012) Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol 30:69–94

    Article  CAS  PubMed  Google Scholar 

  13. Engblom C, Pfirschke C, Zilionis R, Da Silva Martins J, Bos SA, Courties G, Rickelt S, Severe N, Baryawno N, Faget J et al (2017) Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF(high) neutrophils. Science 358

    Google Scholar 

  14. Fankhauser M, Broggi MAS, Potin L, Bordry N, Jeanbart L, Lund AW, Da Costa E, Hauert S, Rincon-Restrepo M, Tremblay C et al (2017) Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma. Sci Transl Med 9

    Google Scholar 

  15. Ferris RL, Lotze MT, Leong SP, Hoon DS, Morton DL (2012) Lymphatics, lymph nodes and the immune system: barriers and gateways for cancer spread. Clin Exp Metastasis 29:729–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Flint TR, Janowitz T, Connell CM, Roberts EW, Denton AE, Coll AP, Jodrell DI, Fearon DT (2016) Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab 24:672–684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gardner A, Ruffell B (2016) Dendritic cells and cancer immunity. Trends Immunol 37:855–865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Garris CS, Arlauckas SP, Kohler RH, Trefny MP, Garren S, Piot C, Engblom C, Pfirschke C, Siwicki M, Gungabeesoon J et al (2018) Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-gamma and IL-12. Immunity 49(1148–1161):e1147

    Google Scholar 

  19. Grabowska J, Lopez-Venegas MA, Affandi AJ, den Haan JMM (2018) CD169(+) macrophages capture and dendritic cells instruct: the interplay of the gatekeeper and the general of the immune system. Front Immunol 9:2472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Han Y, Liu Q, Hou J, Gu Y, Zhang Y, Chen Z, Fan J, Zhou W, Qiu S, Zhang Y et al (2018) Tumor-induced generation of splenic erythroblast-like Ter-cells promotes tumor progression. Cell 173(634–648):e612

    Google Scholar 

  21. Jones D, Pereira ER, Padera TP (2018) Growth and immune evasion of lymph node metastasis. Front Oncol 8:36

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kawada K, Taketo MM (2011) Significance and mechanism of lymph node metastasis in cancer progression. Cancer Res 71:1214–1218

    Article  CAS  PubMed  Google Scholar 

  23. Kohrt HE, Nouri N, Nowels K, Johnson D, Holmes S, Lee PP (2005) Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer. PLoS Med 2:e284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Marigo I, Bosio E, Solito S, Mesa C, Fernandez A, Dolcetti L, Ugel S, Sonda N, Bicciato S, Falisi E et al (2010) Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity 32:790–802

    Article  CAS  PubMed  Google Scholar 

  25. McAllister SS, Gifford AM, Greiner AL, Kelleher SP, Saelzler MP, Ince TA, Reinhardt F, Harris LN, Hylander BL, Repasky EA et al (2008) Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 133:994–1005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. McAllister SS, Weinberg RA (2014) The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol 16:717–727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mendoza A, Fang V, Chen C, Serasinghe M, Verma A, Muller J, Chaluvadi VS, Dustin ML, Hla T, Elemento O et al (2017) Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature 546:158–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Miluzio A, Beugnet A, Grosso S, Brina D, Mancino M, Campaner S, Amati B, de Marco A, Biffo S (2011) Impairment of cytoplasmic eIF6 activity restricts lymphomagenesis and tumor progression without affecting normal growth. Cancer Cell 19:765–775

    Article  CAS  PubMed  Google Scholar 

  29. Morrison SJ, Scadden DT (2014) The bone marrow niche for haematopoietic stem cells. Nature 505:327–334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Moussion C, Mellman I (2018) The dendritic cell strikes back. Immunity 49:997–999

    Article  CAS  PubMed  Google Scholar 

  31. Olmeda D, Cerezo-Wallis D, Riveiro-Falkenbach E, Pennacchi PC, Contreras-Alcalde M, Ibarz N, Cifdaloz M, Catena X, Calvo TG, Canon E et al (2017) Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine. Nature 546:676–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883–891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Petrova TV, Bono P, Holnthoner W, Chesnes J, Pytowski B, Sihto H, Laakkonen P, Heikkila P, Joensuu H, Alitalo K (2008) VEGFR-3 expression is restricted to blood and lymphatic vessels in solid tumors. Cancer Cell 13:554–556

    Article  CAS  PubMed  Google Scholar 

  34. Pucci F, Garris C, Lai CP, Newton A, Pfirschke C, Engblom C, Alvarez D, Sprachman M, Evavold C, Magnuson A et al (2016) SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science 352:242–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pucci F, Rickelt S, Newton AP, Garris C, Nunes E, Evavold C, Pfirschke C, Engblom C, Mino-Kenudson M, Hynes RO et al (2016) PF4 promotes platelet production and lung cancer growth. Cell Rep 17:1764–1772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Riedel A, Shorthouse D, Haas L, Hall BA, Shields J (2016) Tumor-induced stromal reprogramming drives lymph node transformation. Nat Immunol 17:1118–1127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Segura E, Valladeau-Guilemond J, Donnadieu MH, Sastre-Garau X, Soumelis V, Amigorena S (2012) Characterization of resident and migratory dendritic cells in human lymph nodes. J Exp Med 209:653–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sethi N, Kang Y (2011) Unravelling the complexity of metastasis - molecular understanding and targeted therapies. Nat Rev Cancer 11:735–748

    Article  CAS  PubMed  Google Scholar 

  39. Setiadi AF, Ray NC, Kohrt HE, Kapelner A, Carcamo-Cavazos V, Levic EB, Yadegarynia S, van der Loos CM, Schwartz EJ, Holmes S et al (2010) Quantitative, architectural analysis of immune cell subsets in tumor-draining lymph nodes from breast cancer patients and healthy lymph nodes. PLoS ONE 5:e12420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shiota T, Miyasato Y, Ohnishi K, Yamamoto-Ibusuki M, Yamamoto Y, Iwase H, Takeya M, Komohara Y (2016) The clinical significance of CD169-positive lymph node macrophage in patients with breast cancer. PLoS ONE 11:e0166680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, Blanchard D, Bais C, Peale FV, van Bruggen N et al (2007) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450:825–831

    Article  CAS  PubMed  Google Scholar 

  42. Simons DL, Lee G, Kirkwood JM, Lee PP (2011) Interferon signaling patterns in peripheral blood lymphocytes may predict clinical outcome after high-dose interferon therapy in melanoma patients. J Transl Med 9:52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, Madhireddy D, Martins MM, Gherardini PF, Prestwood TR, Chabon J, Bendall SC et al (2017) Systemic immunity is required for effective cancer immunotherapy. Cell 168(487–502):e415

    Google Scholar 

  44. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P et al (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325:612–616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sylman JL, Mitrugno A, Atallah M, Tormoen GW, Shatzel JJ, Tassi Yunga S, Wagner TH, Leppert JT, Mallick P, McCarty OJT (2018) The predictive value of inflammation-related peripheral blood measurements in cancer staging and prognosis. Front Oncol 8:78

    Article  PubMed  PubMed Central  Google Scholar 

  46. Templeton AJ, McNamara MG, Seruga B, Vera-Badillo FE, Aneja P, Ocana A, Leibowitz-Amit R, Sonpavde G, Knox JJ, Tran B et al (2014) Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst 106: dju124

    Google Scholar 

  47. van der Weyden L, Arends MJ, Campbell AD, Bald T, Wardle-Jones H, Griggs N, Velasco-Herrera MD, Tuting T, Sansom OJ, Karp NA et al (2017) Genome-wide in vivo screen identifies novel host regulators of metastatic colonization. Nature 541:233–236

    Google Scholar 

  48. Wang L, Miyahira AK, Simons DL, Lu X, Chang AY, Wang C, Suni MA, Maino VC, Dirbas FM, Yim J et al (2017) IL6 signaling in peripheral blood T cells predicts clinical outcome in breast cancer. Cancer Res 77:1119–1126

    Article  CAS  PubMed  Google Scholar 

  49. Wang et al (2019, September) Connecting blood and intratumoral T reg cell activity in predicting future relapse in breast cancer. Nat Immunol 20(9):1220–1230

    Google Scholar 

  50. Wang et al (2020, January) Breast cancer induces systemic immune changes on cytokine signaling in peripheral blood monocytes and lymphocytes. EBioMedicine 22(52):102631

    Google Scholar 

  51. Wu C, Ning H, Liu M, Lin J, Luo S, Zhu W, Xu J, Wu WC, Liang J, Shao CK et al (2018) Spleen mediates a distinct hematopoietic progenitor response supporting tumor-promoting myelopoiesis. J Clin Investig 128:3425–3438

    Article  PubMed  PubMed Central  Google Scholar 

  52. Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, Carbone DP, Matrisian LM, Richmond A, Lin PC et al (2008) Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+ CD11b+ myeloid cells that promote metastasis. Cancer Cell 13:23–35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhao L, He R, Long H, Guo B, Jia Q, Qin D, Liu SQ, Wang Z, Xiang T, Zhang J et al (2018) Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat Med 24:1536–1544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhou X, Du Y, Huang Z, Xu J, Qiu T, Wang J, Wang T, Zhu W, Liu P (2014) Prognostic value of PLR in various cancers: a meta-analysis. PLoS ONE 9:e101119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zuckerman NS, Yu H, Simons DL, Bhattacharya N, Carcamo-Cavazos V, Yan N, Dirbas FM, Johnson DL, Schwartz EJ, Lee PP (2013) Altered local and systemic immune profiles underlie lymph node metastasis in breast cancer patients. Int J Cancer 132:2537–2547

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Immuno-Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Lei Wang & Peter P. Lee

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  1. Lei Wang
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Correspondence to Peter P. Lee .

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  1. Department of Immuno-Oncology, City of Hope National Medical Center, Duarte, CA, USA

    Peter P. Lee

  2. Refuge Biotechnologies, Menlo Park, CA, USA

    Francesco M. Marincola

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Wang, L., Lee, P.P. (2020). Systemic Correlates of the Tumor Microenvironment. In: Lee, P., Marincola, F. (eds) Tumor Microenvironment. Cancer Treatment and Research, vol 180. Springer, Cham. https://doi.org/10.1007/978-3-030-38862-1_3

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  • DOI: https://doi.org/10.1007/978-3-030-38862-1_3

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