1932

Abstract

The recognition that the immune system can identify and destroy tumor cells has driven a paradigm shift in our understanding of human cancer. Therapies designed to enhance this capacity, including cancer vaccines and coinhibitory receptor blockade, have demonstrated clinical efficacy in treating tumors refractory to conventional therapy. In this review, we discuss how the analysis of the immune microenvironment in primary tissue biopsy samples can be used to stratify patients according to clinical outcome, identify patients likely to benefit from specific immunotherapies, and tailor combination immunotherapy to individual patients and tumor types. As immunotherapy gains in complexity and is used in combination with agents that target oncogenic, intracellular signaling pathways, diagnostic pathologists will play an increasingly important part in identifying and quantifying cellular and molecular biomarkers in tissue samples that reflect the nature and magnitude of the antitumor immune response.

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2016-05-23
2024-04-15
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Literature Cited

  1. Ehrlich P. 1.  1909. Ueber den jetzigen Stand der Karzinomforschung. Ned. Tijdschr. Geneeskd. 5:273–90 [Google Scholar]
  2. Coley WB. 2.  1910. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc. R. Soc. Med. 3:1–48 [Google Scholar]
  3. Burnet M. 3.  1957. Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. BMJ 1:841–47 [Google Scholar]
  4. Thomas L. 4.  1959. Delayed hypersensitivity in health and disease. Cellular and Humoral Aspects of the Hypersensitive States HS Lawrence 529–32 New York: Hoeber-Harper [Google Scholar]
  5. Stutman O. 5.  1974. Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice. Science 183:534–36 [Google Scholar]
  6. Stutman O. 6.  1978. Spontaneous, viral and chemically induced tumors in the nude mouse. The Nude Mouse in Experimental and Clinical Research J Fogh, B Giovanella 411–35 New York: Academic [Google Scholar]
  7. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. 7.  2002. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3:991–98 [Google Scholar]
  8. Dighe AS, Richards E, Old LJ, Schreiber RD. 8.  1994. Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity 1:447–56 [Google Scholar]
  9. Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M. 9.  et al. 1998. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. PNAS 95:7556–61 [Google Scholar]
  10. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE. 10.  et al. 2001. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107–11 [Google Scholar]
  11. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. 11.  2007. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370:59–67 [Google Scholar]
  12. Engels EA, Biggar RJ, Hall HI, Cross H, Crutchfield A. 12.  et al. 2008. Cancer risk in people infected with human immunodeficiency virus in the United States. Int. J. Cancer 123:187–94 [Google Scholar]
  13. Tholey DM, Ahn J. 13.  2015. Impact of hepatitis C virus infection on hepatocellular carcinoma. Gastroenterol. Clin. North Am. 44:761–73 [Google Scholar]
  14. Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW. 14.  2002. Merkel cell carcinoma and HIV infection. Lancet 359:497–98 [Google Scholar]
  15. Feng H, Shuda M, Chang Y, Moore PS. 15.  2008. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319:1096–100 [Google Scholar]
  16. Hofbauer GF, Bouwes Bavinck JN, Euvrard S. 16.  2010. Organ transplantation and skin cancer: basic problems and new perspectives. Exp. Dermatol. 19:473–82 [Google Scholar]
  17. Berg D, Otley CC. 17.  2002. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J. Am. Acad. Dermatol. 47:1–17; quiz 18–20 [Google Scholar]
  18. Euvrard S, Kanitakis J, Claudy A. 18.  2003. Skin cancers after organ transplantation. N. Engl. J. Med. 348:1681–91 [Google Scholar]
  19. De Carlis L, Slim AO, De Gasperi A, Muti G, Giacomoni A. 19.  et al. 2001. Posttransplant lymphoproliferative disorders: report from a single center. Transplant Proc. 33:2815–16 [Google Scholar]
  20. Penn I, First MR. 20.  1999. Merkel's cell carcinoma in organ recipients: report of 41 cases. Transplantation 68:1717–21 [Google Scholar]
  21. Clarke CA, Robbins HA, Tatalovich Z, Lynch CF, Pawlish KS. 21.  et al. 2015. Risk of merkel cell carcinoma after solid organ transplantation. J. Natl. Cancer Inst. 107:dju382 [Google Scholar]
  22. Menon MP, Pittaluga S, Jaffe ES. 22.  2012. The histological and biological spectrum of diffuse large B-cell lymphoma in the World Health Organization classification. Cancer J. 18:411–20 [Google Scholar]
  23. Cohen JI, Kimura H, Nakamura S, Ko YH, Jaffe ES. 23.  2009. Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8–9 September 2008. Ann. Oncol. 20:1472–82 [Google Scholar]
  24. Rabkin CS. 24.  1994. Epidemiology of AIDS-related malignancies. Curr. Opin. Oncol. 6:492–96 [Google Scholar]
  25. Mbulaiteye SM, Parkin DM, Rabkin CS. 25.  2003. Epidemiology of AIDS-related malignancies an international perspective. Hematol. Oncol. Clin. North Am. 17:673–96 [Google Scholar]
  26. Végso G, Hajdu M, Sebestyén A. 26.  2011. Lymphoproliferative disorders after solid organ transplantation—classification, incidence, risk factors, early detection and treatment options. Pathol. Oncol. Res. 17:443–54 [Google Scholar]
  27. Dunn GP, Old LJ, Schreiber RD. 27.  2004. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22:329–60 [Google Scholar]
  28. Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ. 28.  et al. 2007. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903–7 [Google Scholar]
  29. Balkwill F, Mantovani A. 29.  2001. Inflammation and cancer: back to Virchow?. Lancet 357:539–45 [Google Scholar]
  30. Jawad N, Direkze N, Leedham SJ. 30.  2011. Inflammatory bowel disease and colon cancer. Recent Results Cancer Res. 185:99–115 [Google Scholar]
  31. Xie J, Itzkowitz SH. 31.  2008. Cancer in inflammatory bowel disease. World J. Gastroenterol. 14:378–89 [Google Scholar]
  32. Moore OS Jr, Foote FW Jr. 32.  1949. The relatively favorable prognosis of medullary carcinoma of the breast. Cancer 2:635–42 [Google Scholar]
  33. Bulkley GB, Cohen MH, Banks PM, Char DH, Ketcham AS. 33.  1975. Long-term spontaneous regression of malignant melanoma with visceral metastases. Report of a case with immunologic profile. Cancer 36:485–94 [Google Scholar]
  34. Schatton T, Scolyer RA, Thompson JF, Mihm MC Jr. 34.  2014. Tumor-infiltrating lymphocytes and their significance in melanoma prognosis. Methods Mol. Biol. 1102:287–324 [Google Scholar]
  35. Clark WH Jr, From L, Bernardino EA, Mihm MC. 35.  1969. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 29:705–27 [Google Scholar]
  36. Larsen TE, Grude TH. 36.  1978. A retrospective histological study of 669 cases of primary cutaneous malignant melanoma in clinical stage I. I. Histological classification, sex and age of the patients, localization of tumour and prognosis. Acta Pathol. Microbiol. Scand. A 86A:437–50 [Google Scholar]
  37. Day CL Jr, Sober AJ, Kopf AW, Lew RA, Mihm MC Jr. 37.  1981. A prognostic model for clinical stage I melanoma of the upper extremity. The importance of anatomic subsites in predicting recurrent disease. Ann. Surg. 193:436–40 [Google Scholar]
  38. Mihm MC Jr, Clemente CG, Cascinelli N. 38.  1996. Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response. Lab. Invest. 74:43–47 [Google Scholar]
  39. Clark WH Jr, Elder DE, Guerry D IV, Braitman LE, Trock BJ. 39.  et al. 1989. Model predicting survival in stage I melanoma based on tumor progression. J. Natl. Cancer Inst. 81:1893–904 [Google Scholar]
  40. Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N. 40.  1996. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77:1303–10 [Google Scholar]
  41. Kruper LL, Spitz FR, Czerniecki BJ, Fraker DL, Blackwood-Chirchir A. 41.  et al. 2006. Predicting sentinel node status in AJCC stage I/II primary cutaneous melanoma. Cancer 107:2436–45 [Google Scholar]
  42. Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R. 42.  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. 30:2678–83 [Google Scholar]
  43. Sang M, Wang L, Ding C, Zhou X, Wang B. 43.  et al. 2011. Melanoma-associated antigen genes—an update. Cancer Lett. 302:85–90 [Google Scholar]
  44. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S. 44.  et al. 2013. Signatures of mutational processes in human cancer. Nature 500:415–21 [Google Scholar]
  45. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. 45.  2013. Cancer genome landscapes. Science 339:1546–58 [Google Scholar]
  46. Lu YC, Yao X, Crystal JS, Li YF, El-Gamil M. 46.  et al. 2014. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin. Cancer Res. 20:3401–10 [Google Scholar]
  47. Linnemann C, van Buuren MM, Bies L, Verdegaal EM, Schotte R. 47.  et al. 2015. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat. Med. 21:81–85 [Google Scholar]
  48. Graham DM, Appelman HD. 48.  1990. Crohn's-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. Mod. Pathol. 3:332–35 [Google Scholar]
  49. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B. 49.  et al. 2006. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–64 [Google Scholar]
  50. Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G. 50.  et al. 2011. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J. Clin. Oncol. 29:610–18 [Google Scholar]
  51. Galon J, Mlecnik B, Bindea G, Angell HK, Berger A. 51.  et al. 2014. Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J. Pathol. 232:199–209 [Google Scholar]
  52. Anitei MG, Zeitoun G, Mlecnik B, Marliot F, Haicheur N. 52.  et al. 2014. Prognostic and predictive values of the immunoscore in patients with rectal cancer. Clin. Cancer Res. 20:1891–99 [Google Scholar]
  53. Galon J, Pagès F, Marincola FM, Angell HK, Thurin M. 53.  et al. 2012. Cancer classification using the Immunoscore: a worldwide task force. J. Transl. Med. 10:205 [Google Scholar]
  54. Ogino S, Nosho K, Irahara N, Meyerhardt JA, Baba Y. 54.  et al. 2009. Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype. Clin. Cancer Res. 15:6412–20 [Google Scholar]
  55. Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M. 55.  et al. 2010. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J. Pathol. 222:350–66 [Google Scholar]
  56. Tougeron D, Fauquembergue E, Rouquette A, Le Pessot F, Sesboüé R. 56.  et al. 2009. Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations. Mod. Pathol. 22:1186–95 [Google Scholar]
  57. Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. 57.  2011. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br. J. Cancer 105:93–103 [Google Scholar]
  58. Broussard EK, Disis ML. 58.  2011. TNM staging in colorectal cancer: T is for T cell and M is for memory. J. Clin. Oncol. 29:601–3 [Google Scholar]
  59. Fridman WH, Remark R, Goc J, Giraldo NA, Becht E. 59.  et al. 2014. The immune microenvironment: a major player in human cancers. Int. Arch. Allergy Immunol. 164:13–26 [Google Scholar]
  60. Bingle L, Brown NJ, Lewis CE. 60.  2002. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J. Pathol. 196:254–65 [Google Scholar]
  61. Tan KL, Scott DW, Hong F, Kahl BS, Fisher RI. 61.  et al. 2012. Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial. Blood 120:3280–87 [Google Scholar]
  62. Steidl C, Lee T, Shah SP, Farinha P, Han G. 62.  et al. 2010. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N. Engl. J. Med. 362:875–85 [Google Scholar]
  63. Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH. 63.  et al. 2012. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLOS ONE 7:e50946 [Google Scholar]
  64. Komohara Y, Jinushi M, Takeya M. 64.  2014. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 105:1–8 [Google Scholar]
  65. Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ. 65.  et al. 2012. CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin. Cancer Res. 18:3281–92 [Google Scholar]
  66. Alifano M, Mansuet-Lupo A, Lococo F, Roche N, Bobbio A. 66.  et al. 2014. Systemic inflammation, nutritional status and tumor immune microenvironment determine outcome of resected non-small cell lung cancer. PLOS ONE 9:e106914 [Google Scholar]
  67. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M. 67.  et al. 2008. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J. Clin. Oncol. 26:4410–17 [Google Scholar]
  68. Goc J, Fridman WH, Sautès-Fridman C, Dieu-Nosjean MC. 68.  2013. Characteristics of tertiary lymphoid structures in primary cancers. Oncoimmunology 2:e26836 [Google Scholar]
  69. Starnes CO. 69.  1992. Coley's toxins in perspective. Nature 357:11–12 [Google Scholar]
  70. Bukowski RM. 70.  1997. Natural history and therapy of metastatic renal cell carcinoma: the role of interleukin-2. Cancer 80:1198–220 [Google Scholar]
  71. Restifo NP, Rosenberg SA. 71.  1999. Developing recombinant and synthetic vaccines for the treatment of melanoma. Curr. Opin. Oncol. 11:50–57 [Google Scholar]
  72. Ward JE, McNeel DG. 72.  2007. GVAX: an allogeneic, whole-cell, GM-CSF-secreting cellular immunotherapy for the treatment of prostate cancer. Expert Opin. Biol. Ther. 7:1893–902 [Google Scholar]
  73. Ott PA, Fritsch EF, Wu CJ, Dranoff G. 73.  2014. Vaccines and melanoma. Hematol. Oncol. Clin. North Am. 28:559–69 [Google Scholar]
  74. Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG. 74.  et al. 2008. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. PNAS 105:3005–10 [Google Scholar]
  75. Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. 75.  2014. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 15:e257–67 [Google Scholar]
  76. Palucka K, Banchereau J. 76.  2013. Dendritic-cell-based therapeutic cancer vaccines. Immunity 39:38–48 [Google Scholar]
  77. Radford KJ, Tullett KM, Lahoud MH. 77.  2014. Dendritic cells and cancer immunotherapy. Curr. Opin. Immunol. 27:26–32 [Google Scholar]
  78. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM. 78.  et al. 2014. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371:1507–17 [Google Scholar]
  79. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL. 79.  et al. 2013. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368:1509–18 [Google Scholar]
  80. Porter DL, Levine BL, Kalos M, Bagg A, June CH. 80.  2011. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365:725–33 [Google Scholar]
  81. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA. 81.  et al. 2010. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363:711–23 [Google Scholar]
  82. Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K. 82.  et al. 2015. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33:1889–94 [Google Scholar]
  83. Della Vittoria Scarpati G, Fusciello C, Perri F, Sabbatino F, Ferrone S. 83.  et al. 2014. Ipilimumab in the treatment of metastatic melanoma: management of adverse events. OncoTargets Ther. 7:203–9 [Google Scholar]
  84. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC. 84.  et al. 2012. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366:2443–54 [Google Scholar]
  85. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL. 85.  et al. 2012. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366:2455–65 [Google Scholar]
  86. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC. 86.  et al. 2015. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372:311–19 [Google Scholar]
  87. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y. 87.  et al. 2014. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558–62 [Google Scholar]
  88. Postow MA, Callahan MK, Wolchok JD. 88.  2015. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33:1974–82 [Google Scholar]
  89. Lesokhin A, Ansell S, Armand P, Scott E, Halwani A. 89.  et al. 2014. Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies Presented at Annu. Meet. Expo. Am. Soc. Hematol., 56th, San Francisco (Abstr. 291) [Google Scholar]
  90. Schalper KA. 90.  2014. PD-L1 expression and tumor-infiltrating lymphocytes: revisiting the antitumor immune response potential in breast cancer. Oncoimmunology 3:e29288 [Google Scholar]
  91. Ribas A, Comin-Anduix B, Economou JS, Donahue TR. Rocha P. 91. , de la et al. 2009. Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade. Clin. Cancer Res. 15:390–99 [Google Scholar]
  92. Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S. 92.  et al. 2011. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Transl. Med. 9:204 [Google Scholar]
  93. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ. 93.  et al. 2014. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–71 [Google Scholar]
  94. Kittaneh M, Montero AJ, Glück S. 94.  2013. Molecular profiling for breast cancer: a comprehensive review. Biomark Cancer 5:61–70 [Google Scholar]
  95. You YN, Rustin RB, Sullivan JD. 95.  2015. Oncotype DX® colon cancer assay for prediction of recurrence risk in patients with stage II and III colon cancer: a review of the evidence. Surg. Oncol. 24:61–66 [Google Scholar]
  96. Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H. 96.  et al. 2012. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol. Immunother. 61:1019–31 [Google Scholar]
  97. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O. 97.  et al. 2014. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563–67 [Google Scholar]
  98. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM. 98.  et al. 2014. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371:2189–99 [Google Scholar]
  99. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V. 99.  et al. 2015. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 348:124–28 [Google Scholar]
  100. Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG. 100.  et al. 2013. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin. Cancer Res. 19:3462–73 [Google Scholar]
  101. Shi M, Roemer MG, Chapuy B, Liao X, Sun H. 101.  et al. 2014. Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. Am. J. Surg. Pathol. 38:1715–23 [Google Scholar]
  102. Zhang Y, Kang S, Shen J, He J, Jiang L. 102.  et al. 2015. Prognostic significance of programmed cell death 1 (PD-1) or PD-1 ligand 1 (PD-L1). Expression in epithelial-originated cancer: a meta-analysis. Medicine 94:e515 [Google Scholar]
  103. Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A. 103.  et al. 2006. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J. Exp. Med. 203:883–95 [Google Scholar]
  104. Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N. 104.  2006. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 108:19–24 [Google Scholar]
  105. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K. 105.  et al. 2005. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin. Cancer Res. 11:2947–53 [Google Scholar]
  106. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y. 106.  et al. 2007. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. PNAS 104:3360–65 [Google Scholar]
  107. Nomi T, Sho M, Akahori T, Hamada K, Kubo A. 107.  et al. 2007. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 13:2151–57 [Google Scholar]
  108. Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H. 108.  et al. 2005. Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer 104:2084–91 [Google Scholar]
  109. Du Z, Abedalthagafi M, Aizer AA, McHenry AR, Sun HH. 109.  et al. 2015. Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma. Oncotarget 6:4704–16 [Google Scholar]
  110. Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T. 110.  et al. 2010. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116:3268–77 [Google Scholar]
  111. Jones D, Fletcher CD, Pulford K, Shahsafaei A, Dorfman DM. 111.  1999. The T-cell activation markers CD30 and OX40/CD134 are expressed in nonoverlapping subsets of peripheral T-cell lymphoma. Blood 93:3487–93 [Google Scholar]
  112. Anderson MW, Zhao S, Freud AG, Czerwinski DK, Kohrt H. 112.  et al. 2012. CD137 is expressed in follicular dendritic cell tumors and in classical Hodgkin and T-cell lymphomas: diagnostic and therapeutic implications. Am. J. Pathol. 181:795–803 [Google Scholar]
  113. Arce J, Levin M, Xie Q, Albanese J, Ratech H. 113.  2011. T-regulatory cells in lymph nodes: correlation with sex and HIV status. Am. J. Clin. Pathol. 136:35–42 [Google Scholar]
  114. Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P. 114.  et al. 2012. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin. Cancer Res. 18:1611–18 [Google Scholar]
  115. Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M. 115.  et al. 2011. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471:377–81 [Google Scholar]
  116. Twa DD, Chan FC, Ben-Neriah S, Woolcock BW, Mottok A. 116.  et al. 2014. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 123:2062–65 [Google Scholar]
  117. Hao Y, Chapuy B, Monti S, Sun HH, Rodig SJ, Shipp MA. 117.  2014. Selective JAK2 inhibition specifically decreases Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in vitro and in vivo. Clin. Cancer Res. 20:2674–83 [Google Scholar]
  118. Curran MA, Montalvo W, Yagita H, Allison JP. 118.  2010. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. PNAS 107:4275–80 [Google Scholar]
  119. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA. 119.  et al. 2013. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369:122–33 [Google Scholar]
  120. Perez-Gracia JL, Labiano S, Rodriguez-Ruiz ME, Sanmamed MF, Melero I. 120.  2014. Orchestrating immune check-point blockade for cancer immunotherapy in combinations. Curr. Opin. Immunol. 27:89–97 [Google Scholar]
  121. Shin DS, Ribas A. 121.  2015. The evolution of checkpoint blockade as a cancer therapy: What's here, what's next?. Curr. Opin. Immunol. 33:23–35 [Google Scholar]
  122. Brignone C, Escudier B, Grygar C, Marcu M, Triebel F. 122.  2009. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin. Cancer Res. 15:6225–31 [Google Scholar]
  123. Brignone C, Gutierrez M, Mefti F, Brain E, Jarcau R. 123.  et al. 2010. First-line chemoimmunotherapy in metastatic breast carcinoma: Combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J. Transl. Med. 8:71 [Google Scholar]
  124. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M. 124.  et al. 2012. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72:917–27 [Google Scholar]
  125. Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ. 125.  2011. Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors. Cancer Res. 71:3540–51 [Google Scholar]
  126. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. 126.  2010. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207:2187–94 [Google Scholar]
  127. Linch SN, McNamara MJ, Redmond WL. 127.  2015. OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front. Oncol. 5:34 [Google Scholar]
  128. Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L. 128.  et al. 2013. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 73:7189–98 [Google Scholar]
  129. Redmond WL, Linch SN, Kasiewicz MJ. 129.  2014. Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity. Cancer Immunol. Res. 2:142–53 [Google Scholar]
  130. Vanneman M, Dranoff G. 130.  2012. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12:237–51 [Google Scholar]
  131. Boni A, Cogdill AP, Dang P, Udayakumar D, Njauw CN. 131.  et al. 2010. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 70:5213–19 [Google Scholar]
  132. Koya RC, Mok S, Otte N, Blacketor KJ, Comin-Anduix B. 132.  et al. 2012. BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res. 72:3928–37 [Google Scholar]
  133. Liu C, Peng W, Xu C, Lou Y, Zhang M. 133.  et al. 2013. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin. Cancer Res. 19:393–403 [Google Scholar]
  134. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. 134.  2013. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 368:1365–66 [Google Scholar]
  135. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S. 135.  et al. 2013. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 122:2539–49 [Google Scholar]
  136. Ali K, Soond DR, Piñeiro R, Hagemann T, Pearce W. 136.  et al. 2014. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 510:407–11 [Google Scholar]
  137. Johnson DB, Lovly CM, Flavin M, Panageas KS, Ayers GD. 137.  et al. 2015. Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies. Cancer Immunol. Res. 3:288–95 [Google Scholar]
  138. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM. 138.  et al. 2013. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 14:249–56 [Google Scholar]
  139. Héninger E, Krueger TE, Lang JM. 139.  2015. Augmenting antitumor immune responses with epigenetic modifying agents. Front. Immunol. 6:29 [Google Scholar]
  140. Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M. 140.  et al. 2014. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 28:1280–88 [Google Scholar]
  141. Kim K, Skora AD, Li Z, Liu Q, Tam AJ. 141.  et al. 2014. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. PNAS 111:11774–79 [Google Scholar]
  142. Kluger HM, Zito CR, Barr ML, Baine MK, Chiang VL. 142.  et al. 2015. Characterization of PD-L1 expression and associated T-cell infiltrates in metastatic melanoma samples from variable anatomic sites. Clin. Cancer Res. 21:3052–60 [Google Scholar]
  143. Wimberly H, Brown JR, Schalper K, Haack H, Silver MR. 143.  et al. 2015. PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol. Res. 3:326–32 [Google Scholar]
  144. Bendall SC, Simonds EF, Qiu P, Amir el-AD, Krutzik PO. 144.  et al. 2011. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science 332:687–96 [Google Scholar]
  145. Angelo M, Bendall SC, Finck R, Hale MB, Hitzman C. 145.  et al. 2014. Multiplexed ion beam imaging of human breast tumors. Nat. Med. 20:436–42 [Google Scholar]
  146. Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N. 146.  et al. 2008. Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat. Biotechnol. 26:317–25 [Google Scholar]
  147. Carey CD, Gusenleitner D, Chapuy B, Kovach AE, Kluk MJ. 147.  et al. 2015. Molecular classification of MYC-driven B-cell lymphomas by targeted gene expression profiling of fixed biopsy specimens. J. Mol. Diagn. 17:19–30 [Google Scholar]
  148. Scott DW, Wright GW, Williams PM, Lih CJ, Walsh W. 148.  et al. 2014. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 123:1214–17 [Google Scholar]
  149. MacConaill LE, Garcia E, Shivdasani P, Ducar M, Adusumilli R. 149.  et al. 2014. Prospective enterprise-level molecular genotyping of a cohort of cancer patients. J. Mol. Diagn. 16:660–72 [Google Scholar]
  150. Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay J. 150.  et al. 2014. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515:572–76 [Google Scholar]
  151. Ogino S, Galon J, Fuchs CS, Dranoff G. 151.  2011. Cancer immunology—analysis of host and tumor factors for personalized medicine. Nat. Rev. Clin. Oncol. 8:711–19 [Google Scholar]
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