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The Role of the Immune System and Immunoregulatory Mechanisms Relevant to Melanoma

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Genetics of Melanoma

Part of the book series: Cancer Genetics ((CANGENETICS))

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Abstract

A hallmark of melanoma is its inherent immunogenicity through both innate and adaptive immune mechanisms. However, a number of factors inhibit these immune responses through intrinsic mechanisms in tumor cells or adaptive resistance triggered by the immune response via negative feedback. Understanding how these processes are balanced in context of pathways regulating T-cell activation, migration, and differentiation, and T-cell dysfunction in tumors has become a critical area of research. This chapter describes the immunoregulatory mechanisms in the melanoma tumor microenvironment and how positive and negative signaling elements can be harnessed to facilitate enhanced anti-tumor immune responses through immunotherapy.

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References

  1. Frank SA (2002) Immunology and evolution of infectious disease. Princeton University Press, Princeton, NJ

    Google Scholar 

  2. Janeway CAJ, Travers P, Walport M, Shlomchik MJ (2001) Immunobiology: the immune system in health and disease, 5th edn. Garland Science, New York, NY

    Google Scholar 

  3. Schiavoni G, Gabriele L, Mattei F (2013) The tumor microenvironment: a pitch for multiple players. Front Oncol 3:90

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lu C, Kerbel RS (1994) Cytokines, growth factors and the loss of negative growth controls in the progression of human cutaneous malignant melanoma. Curr Opin Oncol 6:212–220

    Article  CAS  PubMed  Google Scholar 

  5. Bar-Eli M (1999) Role of interleukin-8 in tumor growth and metastasis of human melanoma. Pathobiology 67:12–18

    Article  CAS  PubMed  Google Scholar 

  6. Di Cesare S, Marshall JC, Fernandes BF, Logan P, Antecka E, Filho VB, Burnier MN Jr (2007) In vitro characterization and inhibition of the CXCR4/CXCL12 chemokine axis in human uveal melanoma cell lines. Cancer Cell Int 7:17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Mrowietz U, Schwenk U, Maune S et al (1999) The chemokine RANTES is secreted by human melanoma cells and is associated with enhanced tumour formation in nude mice. Br J Cancer 79:1025–1031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bergenwald C, Westermark G, Sander B (1997) Variable expression of tumor necrosis factor alpha in human malignant melanoma localized by in situ hybridization for mRNA. Cancer Immunol Immunother 44:335–340

    Article  CAS  PubMed  Google Scholar 

  9. Harlin H, Meng Y, Peterson AC et al (2009) Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res 69:3077–3085

    Article  CAS  PubMed  Google Scholar 

  10. Balsamo M, Scordamaglia F, Pietra G et al (2009) Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc Natl Acad Sci USA 106:20847–20852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Azimi F, Scolyer RA, Rumcheva P et al (2012) Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol 30:2678–2683

    Article  PubMed  Google Scholar 

  12. Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306

    Article  CAS  PubMed  Google Scholar 

  13. Senovilla L, Vacchelli E, Galon J et al (2012) Trial watch: prognostic and predictive value of the immune infiltrate in cancer. Oncoimmunology 1:1323–1343

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cordova A, Toia F, La Mendola C et al (2012) Characterization of human gammadelta T lymphocytes infiltrating primary malignant melanomas. PLoS One 7:e49878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Metelitsa LS, Wu HW, Wang H et al (2004) Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2. J Exp Med 199:1213–1221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Makitie T, Summanen P, Tarkkanen A, Kivela T (2001) Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci 42:1414–1421

    CAS  PubMed  Google Scholar 

  17. Bronkhorst IH, Ly LV, Jordanova ES, Vrolijk J, Versluis M, Luyten GP, Jager MJ (2011) Detection of M2-macrophages in uveal melanoma and relation with survival. Invest Ophthalmol Vis Sci 52:643–650

    Article  PubMed  Google Scholar 

  18. Martin-Orozco N, Li Y, Wang Y et al (2010) Melanoma cells express ICOS ligand to promote the activation and expansion of T-regulatory cells. Cancer Res 70:9581–9590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gros A, Turcotte S, Wunderlich JR, Ahmadzadeh M, Dudley ME, Rosenberg SA (2012) Myeloid cells obtained from the blood but not from the tumor can suppress T-cell proliferation in patients with melanoma. Clin Cancer Res 18:5212–5223

    Article  CAS  PubMed  Google Scholar 

  20. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF (2013) Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 5:200ra116

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Kerkar SP, Restifo NP (2012) Cellular constituents of immune escape within the tumor microenvironment. Cancer Res 72:3125–3130

    Article  CAS  PubMed  Google Scholar 

  22. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12:253–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Siddiqui SA, Frigola X, Bonne-Annee S et al (2007) Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma. Clin Cancer Res 13:2075–2081

    Article  CAS  PubMed  Google Scholar 

  24. Curiel TJ, Coukos G, Zou L et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  CAS  PubMed  Google Scholar 

  25. Harlin H, Kuna TV, Peterson AC, Meng Y, Gajewski TF (2006) Tumor progression despite massive influx of activated CD8(+) T cells in a patient with malignant melanoma ascites. Cancer Immunol Immunother 55:1185–1197

    Article  CAS  PubMed  Google Scholar 

  26. Appay V, Jandus C, Voelter V et al (2006) New generation vaccine induces effective melanoma-specific CD8+ T cells in the circulation but not in the tumor site. J Immunol 177:1670–1678

    Article  CAS  PubMed  Google Scholar 

  27. Zippelius A, Batard P, Rubio-Godoy V et al (2004) Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 64:2865–2873

    Article  CAS  PubMed  Google Scholar 

  28. Wu RC, Liu S, Chacon JA et al (2012) Detection and characterization of a novel subset of CD8(+)CD57(+) T cells in metastatic melanoma with an incompletely differentiated phenotype. Clin Cancer Res 18:2465–2477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, Spranger S (2013) Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 25:268–276

    Article  CAS  PubMed  Google Scholar 

  30. Messina JL, Fenstermacher DA, Eschrich S et al (2012) 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Sci Rep 2:765

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Cripps JG, Wang J, Maria A, Blumenthal I, Gorham JD (2010) Type 1 T helper cells induce the accumulation of myeloid-derived suppressor cells in the inflamed Tgfb1 knockout mouse liver. Hepatology 52:1350–1359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Romero P, Cerottini JC, Speiser DE (2004) Monitoring tumor antigen specific T-cell responses in cancer patients and phase I clinical trials of peptide-based vaccination. Cancer Immunol Immunother 53:249–255

    Article  PubMed  Google Scholar 

  33. Pilla L, Rivoltini L, Patuzzo R, Marrari A, Valdagni R, Parmiani G (2009) Multipeptide vaccination in cancer patients. Expert Opin Biol Ther 9:1043–1055

    Article  CAS  PubMed  Google Scholar 

  34. van der Bruggen P, Traversari C, Chomez P et al (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254:1643–1647

    Article  PubMed  Google Scholar 

  35. Morgan RA, Chinnasamy N, Abate-Daga D et al (2013) Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 36:133–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jager E, Chen YT, Drijfhout JW et al (1998) Simultaneous humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J Exp Med 187:265–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Anichini A, Maccalli C, Mortarini R et al (1993) Melanoma cells and normal melanocytes share antigens recognized by HLA-A2-restricted cytotoxic T cell clones from melanoma patients. J Exp Med 177:989–998

    Article  CAS  PubMed  Google Scholar 

  38. Matsushita H, Vesely MD, Koboldt DC et al (2012) Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482:400–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Robbins PF, Lu YC, El-Gamil M et al (2013) Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med 19:747–752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Niedobitek G (2000) Epstein-Barr virus infection in the pathogenesis of nasopharyngeal carcinoma. Mol Pathol 53:248–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Muster T, Waltenberger A, Grassauer A et al (2003) An endogenous retrovirus derived from human melanoma cells. Cancer Res 63:8735–8741

    CAS  PubMed  Google Scholar 

  42. Schanab O, Humer J, Gleiss A et al (2011) Expression of human endogenous retrovirus K is stimulated by ultraviolet radiation in melanoma. Pigment Cell Melanoma Res 24:656–665

    Article  CAS  PubMed  Google Scholar 

  43. Serafino A, Balestrieri E, Pierimarchi P et al (2009) The activation of human endogenous retrovirus K (HERV-K) is implicated in melanoma cell malignant transformation. Exp Cell Res 315:849–862

    Article  CAS  PubMed  Google Scholar 

  44. Schiavetti F, Thonnard J, Colau D, Boon T, Coulie PG (2002) A human endogenous retroviral sequence encoding an antigen recognized on melanoma by cytolytic T lymphocytes. Cancer Res 62:5510–5516

    CAS  PubMed  Google Scholar 

  45. Trinchieri G (2012) Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu Rev Immunol 30:677–706

    Article  CAS  PubMed  Google Scholar 

  46. Dunn JH, Ellis LZ, Fujita M (2012) Inflammasomes as molecular mediators of inflammation and cancer: potential role in melanoma. Cancer Lett 314:24–33

    Article  CAS  PubMed  Google Scholar 

  47. Melnikova VO, Bar-Eli M (2009) Inflammation and melanoma metastasis. Pigment Cell Melanoma Res 22:257–267

    Article  CAS  PubMed  Google Scholar 

  48. Richmond A, Yang J, Su Y (2009) The good and the bad of chemokines/chemokine receptors in melanoma. Pigment Cell Melanoma Res 22:175–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dore JF, Pedeux R, Boniol M, Chignol MC, Autier P (2001) Intermediate-effect biomarkers in prevention of skin cancer. IARC Sci Publ 154:81–91

    CAS  PubMed  Google Scholar 

  50. Zaidi MR, Davis S, Noonan FP et al (2011) Interferon-gamma links ultraviolet radiation to melanomagenesis in mice. Nature 469:548–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ahmed B, Van Den Oord JJ (2000) Expression of the inducible isoform of nitric oxide synthase in pigment cell lesions of the skin. Br J Dermatol 142:432–440

    Article  CAS  PubMed  Google Scholar 

  52. Kuchel JM, Barnetson RS, Halliday GM (2003) Nitric oxide appears to be a mediator of solar-simulated ultraviolet radiation-induced immunosuppression in humans. J Invest Dermatol 121:587–593

    Article  CAS  PubMed  Google Scholar 

  53. Grimm EA, Sikora AG, Ekmekcioglu S (2013) Molecular pathways: inflammation-associated nitric-oxide production as a cancer-supporting redox mechanism and a potential therapeutic target. Clin Cancer Res 19:5557–5563

    Article  CAS  PubMed  Google Scholar 

  54. Grimm EA, Ellerhorst J, Tang CH, Ekmekcioglu S (2008) Constitutive intracellular production of iNOS and NO in human melanoma: possible role in regulation of growth and resistance to apoptosis. Nitric Oxide 19:133–137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ekmekcioglu S, Ellerhorst J, Smid CM, Prieto VG, Munsell M, Buzaid AC, Grimm EA (2000) Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival. Clin Cancer Res 6:4768–4775

    CAS  PubMed  Google Scholar 

  56. Bonafe M, Storci G, Franceschi C (2012) Inflamm-aging of the stem cell niche: breast cancer as a paradigmatic example: breakdown of the multi-shell cytokine network fuels cancer in aged people. Bioessays 34:40–49

    Article  CAS  PubMed  Google Scholar 

  57. Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM (2010) Aging of the innate immune system. Curr Opin Immunol 22:507–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann NY Acad Sci 908:244–254

    Article  CAS  PubMed  Google Scholar 

  59. Goldszmid RS, Trinchieri G (2012) The price of immunity. Nat Immunol 13:932–938

    Article  CAS  PubMed  Google Scholar 

  60. Burnet M (1957) Cancer; a biological approach. I. The processes of control. Br Med J 1:779–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Burnet M (1957) Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br Med J 1:841–847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Miller JF (1961) Immunological function of the thymus. Lancet 2:748–749

    Article  CAS  PubMed  Google Scholar 

  63. Stutman O (1974) Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice. Science 183:534–536

    Article  CAS  PubMed  Google Scholar 

  64. Stutman O (1975) Delayed tumour appearance and absence of regression in nude mice infected with murine sarcoma virus. Nature 253:142–144

    Article  CAS  PubMed  Google Scholar 

  65. Stutman O (1979) Chemical carcinogenesis in nude mice: comparison between nude mice from homozygous matings and heterozygous matings and effect of age and carcinogen dose. J Natl Cancer Inst 62:353–358

    CAS  PubMed  Google Scholar 

  66. Seki S, Takeda K, Abo T (1995) The function and role of extrathymic T cells. Nihon Rinsho 53:2846–2857

    CAS  PubMed  Google Scholar 

  67. Budzynski W, Radzikowski C (1994) Cytotoxic cells in immunodeficient athymic mice. Immunopharmacol Immunotoxicol 16:319–346

    Article  CAS  PubMed  Google Scholar 

  68. Pawelec G (1994) MHC-unrestricted immune surveillance of leukemia. Cancer Biother 9:265–288

    Article  CAS  PubMed  Google Scholar 

  69. Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD (1998) Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 95:7556–7561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD (2001) IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107–1111

    Article  CAS  PubMed  Google Scholar 

  71. Vesely MD, Schreiber RD (2013) Cancer immunoediting: antigens, mechanisms, and implications to cancer immunotherapy. Ann NY Acad Sci 1284:1–5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570

    Article  CAS  PubMed  Google Scholar 

  73. Dunn GP, Bruce AT, Sheehan KC et al (2005) A critical function for type I interferons in cancer immunoediting. Nat Immunol 6:722–729

    Article  CAS  PubMed  Google Scholar 

  74. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–998

    Article  CAS  PubMed  Google Scholar 

  75. Smyth MJ, Crowe NY, Godfrey DI (2001) NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol 13:459–463

    Article  CAS  PubMed  Google Scholar 

  76. Landsberg J, Kohlmeyer J, Renn M et al (2012) Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 490:412–416

    Article  CAS  PubMed  Google Scholar 

  77. Caramel J, Papadogeorgakis E, Hill L et al (2013) A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 24:466–480

    Article  CAS  PubMed  Google Scholar 

  78. Garrido MC, Requena L, Kutzner H, Ortiz P, Perez-Gomez B, Rodriguez-Peralto JL (2014) Desmoplastic melanoma: expression of epithelial-mesenchymal transition-related proteins. Am J Dermatopathol 36:238–242

    Article  PubMed  Google Scholar 

  79. Taddei ML, Giannoni E, Morandi A et al (2014) Mesenchymal to amoeboid transition is associated with stem-like features of melanoma cells. Cell Commun Signal 12:24

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Dou J, He X, Liu Y et al (2014) Effect of downregulation of ZEB1 on vimentin expression, tumour migration and tumourigenicity of melanoma B16F10 cells and CSCs. Cell Biol Int 38:452–461

    Article  CAS  PubMed  Google Scholar 

  81. Pulido J, Kottke T, Thompson J et al (2012) Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. Nat Biotechnol 30:337–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Roesch A, Fukunaga-Kalabis M, Schmidt EC et al (2010) A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141:583–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Rodriguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB, Ochoa AC (2002) Regulation of T cell receptor CD3zeta chain expression by L-arginine. J Biol Chem 277:21123–21129

    Article  CAS  PubMed  Google Scholar 

  84. Rodriguez PC, Quiceno DG, Ochoa AC (2007) L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109:1568–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nagaraj S, Gupta K, Pisarev V et al (2007) Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 13:828–835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sinha P, Clements VK, Bunt SK, Albelda SM, Ostrand-Rosenberg S (2007) Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J Immunol 179:977–983

    Article  CAS  PubMed  Google Scholar 

  87. Li H, Han Y, Guo Q, Zhang M, Cao X (2009) Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol 182:240–249

    Article  CAS  PubMed  Google Scholar 

  88. Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ishida T, Ueda R (2006) CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci 97:1139–1146

    Article  CAS  PubMed  Google Scholar 

  90. Kimpfler S, Sevko A, Ring S et al (2009) Skin melanoma development in ret transgenic mice despite the depletion of CD25+Foxp3+ regulatory T cells in lymphoid organs. J Immunol 183:6330–6337

    Article  CAS  PubMed  Google Scholar 

  91. Strauss L, Bergmann C, Whiteside TL (2009) Human circulating CD4+CD25highFoxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis. J Immunol 182:1469–1480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Strauss L, Bergmann C, Szczepanski MJ, Lang S, Kirkwood JM, Whiteside TL (2008) Expression of ICOS on human melanoma-infiltrating CD4+CD25highFoxp3+ T regulatory cells: implications and impact on tumor-mediated immune suppression. J Immunol 180:2967–2980

    Article  CAS  PubMed  Google Scholar 

  93. Zitvogel L, Kepp O, Galluzzi L, Kroemer G (2012) Inflammasomes in carcinogenesis and anticancer immune responses. Nat Immunol 13:343–351

    Article  CAS  PubMed  Google Scholar 

  94. Zarek PE, Huang CT, Lutz ER et al (2008) A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111:251–259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Qureshi OS, Zheng Y, Nakamura K et al (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332:600–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Derre L, Rivals JP, Jandus C et al (2010) BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. J Clin Invest 120:157–167

    Article  CAS  PubMed  Google Scholar 

  97. Uyttenhove C, Pilotte L, Theate I et al (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9:1269–1274

    Article  CAS  PubMed  Google Scholar 

  98. Brody JR, Costantino CL, Berger AC et al (2009) Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle 8:1930–1934

    Article  CAS  PubMed  Google Scholar 

  99. Simpson RJ, Jensen SS, Lim JW (2008) Proteomic profiling of exosomes: current perspectives. Proteomics 8:4083–4099

    Article  CAS  PubMed  Google Scholar 

  100. Lasser C, Eldh M, Lotvall J (2012) Isolation and characterization of RNA-containing exosomes. J Vis Exp 59:e3037

    PubMed  Google Scholar 

  101. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

    Article  CAS  PubMed  Google Scholar 

  102. Hood JL, San RS, Wickline SA (2011) Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 71:3792–3801

    Article  CAS  PubMed  Google Scholar 

  103. Peinado H, Aleckovic M, Lavotshkin S 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 

  104. Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (2006) Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol 176:284–290

    Article  CAS  PubMed  Google Scholar 

  105. Rosenberg SA (1999) A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10:281–287

    Article  CAS  PubMed  Google Scholar 

  106. Kvistborg P, Shu CJ, Heemskerk B et al (2012) TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients. Oncoimmunology 1:409–418

    Article  PubMed  PubMed Central  Google Scholar 

  107. Rosenberg SA, Yannelli JR, Yang JC et al (1994) Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst 86:1159–1166

    Article  CAS  PubMed  Google Scholar 

  108. Rosenberg SA, Yang JC, Topalian SL et al (1994) Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271:907–913

    Article  CAS  PubMed  Google Scholar 

  109. Zhang H, Chua KS, Guimond M et al (2005) Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med 11:1238–1243

    Article  CAS  PubMed  Google Scholar 

  110. Parmiani G, Rivoltini L, Andreola G, Carrabba M (2000) Cytokines in cancer therapy. Immunol Lett 74:41–44

    Article  CAS  PubMed  Google Scholar 

  111. Poust JC, Woolery JE, Green MR (2013) Management of toxicities associated with high-dose interleukin-2 and biochemotherapy. Anticancer Drugs 24:1–13

    Article  CAS  PubMed  Google Scholar 

  112. Levin AM, Bates DL, Ring AM et al (2012) Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature 484:529–533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Carmenate T, Pacios A, Enamorado M, Moreno E, Garcia-Martinez K, Fuente D, Leon K (2013) Human IL-2 mutein with higher antitumor efficacy than wild type IL-2. J Immunol 190:6230–6238

    Article  CAS  PubMed  Google Scholar 

  114. Heaton KM, Ju G, Grimm EA (1993) Human interleukin 2 analogues that preferentially bind the intermediate-affinity interleukin 2 receptor lead to reduced secondary cytokine secretion: implications for the use of these interleukin 2 analogues in cancer immunotherapy. Cancer Res 53:2597–2602

    CAS  PubMed  Google Scholar 

  115. Heaton KM, Rippon MB, El-Naggar A, Tucker SL, Ross MI, Balch CM (1993) Prognostic implications of DNA index in patients with stage III cutaneous melanoma. Am J Surg 166:648–652 (discussion 652–643)

    Article  CAS  PubMed  Google Scholar 

  116. Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4:11–22

    Article  CAS  PubMed  Google Scholar 

  117. Tarhini AA, Gogas H, Kirkwood JM (2012) IFN-alpha in the treatment of melanoma. J Immunol 189:3789–3793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Schwartzentruber DJ, Lawson DH, Richards JM et al (2011) gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 364:2119–2127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lu YC, Yao X, Li YF et al (2013) Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression. J Immunol 190:6034–6042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hailemichael Y, Dai Z, Jaffarzad N et al (2013) Persistent antigen at vaccination sites induces tumor-specific CD8(+) T cell sequestration, dysfunction and deletion. Nat Med 19:465–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Klechevsky E, Banchereau J (2013) Human dendritic cells subsets as targets and vectors for therapy. Ann NY Acad Sci 1284:24–30

    Article  CAS  PubMed  Google Scholar 

  122. Taylor DD, Gercel-Taylor C (2011) Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol 33:441–454

    Article  CAS  PubMed  Google Scholar 

  123. Roberson CD, Atay S, Gercel-Taylor C, Taylor DD (2010) Tumor-derived exosomes as mediators of disease and potential diagnostic biomarkers. Cancer Biomark 8:281–291

    CAS  PubMed  Google Scholar 

  124. Taylor DD, Gercel-Taylor C (2005) Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects. Br J Cancer 92:305–311

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Mears R, Craven RA, Hanrahan S et al (2004) Proteomic analysis of melanoma-derived exosomes by two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. Proteomics 4:4019–4031

    Article  CAS  PubMed  Google Scholar 

  126. Yang C, Kim SH, Bianco NR, Robbins PD (2011) Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model. PLoS One 6:e22517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hodi FS, O'Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hamid O, Robert C, Daud A et al (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Brahmer JR, Tykodi SS, Chow LQ et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Redmond WL, Triplett T, Floyd K, Weinberg AD (2012) Dual anti-OX40/IL-2 therapy augments tumor immunotherapy via IL-2R-mediated regulation of OX40 expression. PLoS One 7:e34467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD (2002) Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci USA 99:16168–16173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Chapuis AG, Thompson JA, Margolin KA et al (2012) Transferred melanoma-specific CD8+ T cells persist, mediate tumor regression, and acquire central memory phenotype. Proc Natl Acad Sci USA 109:4592–4597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Hunder NN, Wallen H, Cao J et al (2008) Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 358:2698–2703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Muranski P, Restifo NP (2009) Adoptive immunotherapy of cancer using CD4(+) T cells. Curr Opin Immunol 21:200–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Rosenberg SA, Packard BS, Aebersold PM et al (1988) Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 319:1676–1680

    Article  CAS  PubMed  Google Scholar 

  137. Dudley ME, Yang JC, Sherry R et al (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26:5233–5239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Besser MJ, Shapira-Frommer R, Treves AJ et al (2010) Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res 16:2646–2655

    Article  CAS  PubMed  Google Scholar 

  139. Radvanyi LG, Bernatchez C, Zhang M et al (2012) Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res 18:6758–6770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Dudley ME, Gross CA, Somerville RP et al (2013) Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol 31:2152–2159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Zhang L, Feldman SA, Zheng Z et al (2012) Evaluation of gamma-retroviral vectors that mediate the inducible expression of IL-12 for clinical application. J Immunother 35:430–439

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Morgan RA, Dudley ME, Wunderlich JR et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Johnson LA, Morgan RA, Dudley ME et al (2009) Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114:535–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3:95ra73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Grupp SA, Kalos M, Barrett D et al (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Kochenderfer JN, Dudley ME, Feldman SA et al (2012) B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119:2709–2720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA (2010) Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18:843–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Yvon E, Del Vecchio M, Savoldo B et al (2009) Immunotherapy of metastatic melanoma using genetically engineered GD2-specific T cells. Clin Cancer Res 15:5852–5860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Lo AS, Ma Q, Liu DL, Junghans RP (2010) Anti-GD3 chimeric sFv-CD28/T-cell receptor zeta designer T cells for treatment of metastatic melanoma and other neuroectodermal tumors. Clin Cancer Res 16:2769–2780

    Article  CAS  PubMed  Google Scholar 

  150. Angell H, Galon J (2013) From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol 25:261–267

    Article  CAS  PubMed  Google Scholar 

  151. Reis PP, Waldron L, Goswami RS et al (2011) mRNA transcript quantification in archival samples using multiplexed, color-coded probes. BMC Biotechnol 11:46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Beard RE, Abate-Daga D, Rosati SF, Zheng Z, Wunderlich JR, Rosenberg SA, Morgan RA (2013) Gene expression profiling using nanostring digital RNA counting to identify potential target antigens for melanoma immunotherapy. Clin Cancer Res 19:4941–4950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Tanese K, Grimm EA, Ekmekcioglu S (2012) The role of melanoma tumor-derived nitric oxide in the tumor inflammatory microenvironment: its impact on the chemokine expression profile, including suppression of CXCL10. Int J Cancer 131:891–901

    Article  CAS  PubMed  Google Scholar 

  154. Mann GJ, Pupo GM, Campain AE et al (2013) BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene profile predict poor outcome in patients with stage III melanoma. J Invest Dermatol 133:509–517

    Article  CAS  PubMed  Google Scholar 

  155. Marzese DM, Scolyer RA, Huynh JL et al (2014) Epigenome-wide DNA methylation landscape of melanoma progression to brain metastasis reveals aberrations on homeobox D cluster associated with prognosis. Hum Mol Genet. 1;23(1):226–38

    Google Scholar 

  156. Griewank KG, Ugurel S, Schadendorf D, Paschen A (2013) New developments in biomarkers for melanoma. Curr Opin Oncol 25:145–151

    Article  CAS  PubMed  Google Scholar 

  157. Gajewski TF, Louahed J, Brichard VG (2010) Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J 16:399–403

    Article  CAS  PubMed  Google Scholar 

  158. Ji RR, Chasalow SD, Wang L et al (2012) An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother 61:1019–1031

    Article  CAS  PubMed  Google Scholar 

  159. Ahmadzadeh M, Felipe-Silva A, Heemskerk B, Powell DJ Jr, Wunderlich JR, Merino MJ, Rosenberg SA (2008) FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions. Blood 112:4953–4960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Galon J, Pages F, Marincola FM et al (2012) Cancer classification using the immunoscore: a worldwide task force. J Transl Med 10:205

    Article  PubMed  PubMed Central  Google Scholar 

  161. Galon J, Pages F, Marincola FM et al (2012) The immune score as a new possible approach for the classification of cancer. J Transl Med 10:1

    Article  PubMed  PubMed Central  Google Scholar 

  162. Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G (2011) Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res 71:5601–5605

    Article  CAS  PubMed  Google Scholar 

  163. Gajewski TF, Meng Y, Harlin H (2006) Immune suppression in the tumor microenvironment. J Immunother 29:233–240

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Melanoma Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Cara Haymaker PhD, Geok Choo Sim PhD, Marie-Andree Forget PhD, Jie Qing Chen, Chantale Bernatchez PhD & Laszlo Radvanyi

  2. Moffit Cancer Center, Tampa, FL, USA

    Geok Choo Sim PhD

  3. Lion Biotechnologies, Tampa, FL, USA

    Jie Qing Chen

  4. EMD Serono Research and Development Institute, Billerica, MA, USA

    Laszlo Radvanyi

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  1. Cara Haymaker PhD
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  2. Geok Choo Sim PhD
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  3. Marie-Andree Forget PhD
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  4. Jie Qing Chen
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  5. Chantale Bernatchez PhD
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  6. Laszlo Radvanyi
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Editors and Affiliations

  1. Chief of Dermatopathology Section, Associate Professor of Pathology and Der, Houston, Texas, USA

    Carlos A. Torres-Cabala

  2. The University of Texas MD Anderson Canc, Associate Professor of Pathology and Der, Houston, Texas, USA

    Jonathan L. Curry

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Haymaker, C., Sim, G.C., Forget, MA., Chen, J.Q., Bernatchez, C., Radvanyi, L. (2016). The Role of the Immune System and Immunoregulatory Mechanisms Relevant to Melanoma. In: Torres-Cabala, C., Curry, J. (eds) Genetics of Melanoma. Cancer Genetics. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3554-3_2

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