Implications of the tumor immune microenvironment for staging and therapeutics

Modern Pathology

Volumn 31, Issue 2, 2018, Pages 214-234

  Taube, Janis M ^a   Galon, Jérôme ^b,c,d   Sholl, Lynette M ^e   Rodig, Scott J ^e   Cottrell, Tricia R ^a   Giraldo, Nicolas A ^a   Baras, Alexander S ^a   Patel, Sanjay S ^e   Anders, Robert A ^a   Rimm, David L ^f   Cimino Mathews, Ashley ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b INSERM   (France)

^c UNIVERSITÉ PARIS DESCARTES   (France)

^d SORBONNE UNIVERSITÉ   (France)

^e BRIGHAM AND WOMEN S HOSPITAL   (United States)

^f YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD8 ANTIGEN; IMMUNE CHECKPOINT INHIBITOR; IMMUNOMODULATING AGENT; PROGRAMMED DEATH 1 LIGAND 1; PROGRAMMED DEATH 1 RECEPTOR; TUMOR MARKER; UNCLASSIFIED DRUG;

BREAST CARCINOMA; CANCER IMMUNOTHERAPY; CANCER PROGNOSIS; CANCER STAGING; CANCER TISSUE; CD8+ T LYMPHOCYTE; COLORECTAL CARCINOMA; CYTOTOXIC T LYMPHOCYTE; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HELPER CELL; HEMATOLOGIC MALIGNANCY; HISTOPATHOLOGY; HODGKIN DISEASE; HUMAN; IMMUNE RESPONSE; IMMUNOHISTOCHEMISTRY; MELANOMA; MUTATIONAL LOAD; NON SMALL CELL LUNG CANCER; PATHOLOGIST; PRIORITY JOURNAL; RENAL CELL CARCINOMA; REVIEW; SKIN CANCER; TH1 CELL LINE; TRANSITIONAL CELL CARCINOMA; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; GENETICS; IMMUNOLOGY; NEOPLASM; PATHOLOGY; PROGNOSIS; TUMOR ASSOCIATED LEUKOCYTE;

BIOMARKERS, TUMOR; HUMANS; LYMPHOCYTES, TUMOR-INFILTRATING; NEOPLASM STAGING; NEOPLASMS; PROGNOSIS; TUMOR MICROENVIRONMENT;

EID: 85041813538     PISSN: 08933952     EISSN: 15300285     Source Type: Journal    
DOI: 10.1038/modpathol.2017.156     Document Type: Review

References (165)

1. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013;14:1014-1022.
2. Vesely MD, Kershaw MH, Schreiber RD, et al. Natural innate and adaptive immunity to cancer. Annu Rev Immunol 2011;29:235-271.
3. Fridman WH, Pages F, Sautes-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012;12:298-306.
4. 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;313:1960-1964.
5. Angell H, Galon J. From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol 2013;25:261-267.
6. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006;439:682-687.
7. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 2012;4:127ra137.
8. Velcheti V, Schalper KA, Carvajal DE, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest 2014;94:107-116.
9. Lipson EJ, Vincent JG, Loyo M, et al. PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res 2013;1:54-63.
10. Cimino-Mathews A, Thompson E, Taube JM, et al. PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum Pathol 2016;47:52-63.
11. Schalper KA, elcheti V, Carvajal D, et al. In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res 2014;20:2773-2782.
12. Yanik EL, Kaunitz GJ, Cottrell TR, et al. Association of HIV status with local immune response to anal squamous cell carcinoma: implications for immunotherapy. JAMA Oncol 2017;3:974-978.
13. Chen CL, Pan QZ, Zhao JJ, et al. PD-L1 expression as a predictive biomarker for cytokine-induced killer cell immunotherapy in patients with hepatocellular carcinoma. Oncoimmunology 2016;5: e1176653.
14. Xu C, Fillmore CM, Koyama S, et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 2014;25: 590-604.
15. Parsa AT, Waldron JS, Panner A, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 2007;13:84-8.
16. Green MR, Monti S, Rodig SJ, et al. 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 2010;116:3268-3277.
17. Lastwika KJ, Wilson W 3rd, Li QK, et al. Control of PD-L1 expression by oncogenic activation of the AKTmTOR pathway in non-small cell lung cancer. Cancer Res 2016;76:227-238.
18. Van Allen EM, Golay HG, Liu Y, et al. Long-term benefit of PD-L1 blockade in lung cancer associated with JAK3 activation. Cancer Immunol Res 2015;3: 855-863.
19. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res 2012;18:1611-1618.
20. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12: 252-264.
21. Topalian SL, Taube JM, Anders RA, et al. Mechanismdriven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 2016;16: 275-287.
22. Littman DR. Releasing the brakes on cancer immunotherapy. Cell 2015;162:1186-1190.
23. Ribas A. Releasing the brakes on cancer immunotherapy. N Engl J Med. 2015;373:1490-1492.
24. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014;32:1020-1030.
25. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 2015;33: 1889-1894.
26. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364: 2507-2516.
27. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366:707-714.
28. Lipson EJ, Sharfman WH, Drake CG, et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 2013;19:462-468.
29. Chiou VL, Burotto M. Pseudoprogression and immune-related response in solid tumors. J Clin Oncol 2015;33:3541-3543.
30. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369:134-144.
31. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372:2006-2017.
32. Hodi FS, Chesney J, Pavlick AC, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 2016;17: 1558-1568.
33. Sunshine J, Taube JM. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol 2015;23:32-38.
34. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568-571.
35. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-2520.
36. Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348: 124-128.
37. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014;371:2189-2199.
38. Hugo W, Zaretsky JM, Sun L, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 2016;165: 35-44.
39. Shin DS, Zaretsky JM, Escuin-Ordinas H, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 2017;7:188-201.
40. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 2016;375:819-829.
41. Galon J, Mlecnik B, Bindea G, et al. Towards the introduction of the 'Immunoscore' in the classification of malignant tumours. J Pathol 2014;232:199-209.
42. Mlecnik B, Tosolini M, Kirilovsky A, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 2011;29:610-618.
43. Pagès F, Kirilovsky A, Mlecnik B, et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009;27:5944-51.
44. Galon J, Mlecnik B, Marliot F, et al. Validation of the Immunoscore (IM) as a prognostic marker in stage I/II/ III colon cancer: results of a worldwide consortiumbased analysis of 1, 336 patients. J Clin Oncol 2016;34 (Suppl):abstr 3500.
45. Mlecnik B, Bindea G, Angell HK, et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 2016;44:698-711.
46. Berghoff AS, Fuchs E, Ricken G, et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology 2016;5: e1057388.
47. Galon J, Franck P, Marincola FM, et al. Cancer classification using the Immunoscore: a worldwide task force. J Transl Med 2012;10:205.
48. Galon J, Pages F, Marincola FM, et al. The immune score as a new possible approach for the classification of cancer. J Transl Med 2012;10:1.
49. Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project. J Thorac Oncol 2017;12: 208-222.
50. Ratcliffe MJ, Sharpe A, Midha A, et al. Agreement between programmed cell death ligand-1 diagnostic assays across multiple protein expression cut-offs in non-small cell lung cancer. Clin Cancer Res 2017;23: 3585-3591.
51. Rimm DL, Han G, Taube JM, et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol 2017;3: 1051-1058.
52. Scheel AH, Dietel M, Heukamp LC, et al. Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas. Mod Pathol 2016;29:1165-1172.
53. Gaule P, Smithy JW, Toki M, et al. A quantitative comparison of antibodies to programmed cell death 1 ligand 1. JAMA Oncol 2017;3:256-259.
54. Sunshine JC, Nguyen P, Kaunitz G, et al. PD-L1 Expression in melanoma: a quantitative immunohistochemical antibody comparison. Clin Cancer Res 2017;23:4938-4944.
55. Socinski M, Creelan B, Horn L, et al. NSCLC, metastatic CheckMate 026: a phase 3 trial of nivolumab vs investigator's choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage iv/recurrent programmed death ligand 1 (PDL1) - positive NSCLC. Ann Oncol 2016;27(suppl-6): LBA7-PR.
56. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1- positive non-small-cell lung cancer. N Engl J Med 2016;375:1823-1833.
57. McLaughlin J, Han G, Schalper KA, et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol 2016;2:46-54.
58. Rehman JA, Han G, Carvajal-Hausdorf DE, et al. Quantitative and pathologist-read comparison of the heterogeneity of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer. Mod Pathol 2017;30:340-349.
59. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 2016;17:1283-1294.
60. Nayak L, Iwamoto FM, LaCasce A, et al. PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 2017;129:3071-3073.
61. Howitt BE, Sun HH, Roemer MG, et al. Genetic basis for PD-L1 expression in squamous cell carcinomas of the cervix and vulva. JAMA Oncol 2016;2:518-522.
62. Jarvinen AK, Autio R, Kilpinen S, et al. Highresolution copy number and gene expression microarray analyses of head and neck squamous cell carcinoma cell lines of tongue and larynx. Genes Chromosomes Cancer 2008;47:500-509.
63. Piha-Paul SA, Bennouna J, Albright A, et al. T-cell inflamed phenotype gene expression signatures to predict clinical benefit from pembrolizumab across multiple tumor types. J Clin Oncol 2016;34 (suppl):1536-1536.
64. Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma. N Engl J Med 2016;374:2542-2552.
65. Schalper KA, Brown J, Carvajal-Hausdorf D, et al. Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst 2015;107:dju435.
66. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-723.
67. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015;16:908-918.
68. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521-2532.
69. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015;373:23-34.
70. Kaunitz G, Cottrell T, Lilo M, et al. Melanoma subtypes demonstrate distinct PD-L1 expression profiles. Lab Invest 2017;97:1063-1071.
71. Taube JM, Young GD, McMiller TL, et al. Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade. Clin Cancer Res 2015;21: 3969-3976.
72. Rodic N, Anders RA, Eshleman JR., et al. PD-L1 expression in melanocytic lesions does not correlate with the BRAF V600E mutation. Cancer Immunol Res 2015;3:110-115.
73. Danilova L, Wang H, Sunshine J, et al. Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors. Proc Natl Acad Sci USA 2016;113: E7769-E77.
74. Obeid JM, Erdag G, Smolkin ME, et al. PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: correlation with tumor-infiltrating immune cells and clinical outcome. Oncoimmunology 2016;5:e1235107.
75. Daud AI, Wolchok JD, Robert C, et al. Programmed death-ligand 1 expression and response to the antiprogrammed death 1 antibody pembrolizumab in melanoma. J Clin Oncol 2016;34:4102-4109.
76. Johnson DB, Bordeaux J, Kim JY, et al. Quantitative spatial profiling of PD-1/PD-L1 interaction and HLA-DR/IDO-1 predicts improved outcomes to anti- PD-1 in metastatic melanoma. J Clin Oncol 2017;35:9517-9517.
77. Roh W, Chen PL, Reuben A, et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci Transl Med 2017;9: eaah3560.
78. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016;17: 1374-1385.
79. Giraldo N, Kaunitz G, Cottrell T, et al. The differential association of PD-1, PD-L1, and CD8+ cells with presence of Merkel cell polyomavirus and response to pembrolizumab in patients with Merkel cell carcinoma (MCC). Cancer Res 2017;77:662-662.
80. Lipson EJ, Lilo MT, Ogurtsova A, et al. Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade. J Immunother Cancer 2017;5:23.
81. Falchook GS, Leidner R, Stankevich E, et al. Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti-PD1 monoclonal antibody REGN2810. J Immunother Cancer 2016;4:70.
82. Lipson EJ, Bagnasco SM, Moore J Jr., et al. Tumor regression and allograft rejection after administration of anti-PD-1. N Engl J Med 2016;374:896-898.
83. Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Adv Exp Med Biol 2016;893:1-19.
84. Masters GA, Temin S, Azzoli CG, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol 2015;33:3488-3515.
85. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:1998-2006.
86. Shaw AT, Ou SH, Bang YJ, et al. Crizotinib in ROS1- rearranged non-small-cell lung cancer. N Engl J Med 2014;371:1963-1671.
87. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-2028.
88. 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: 563-567.
89. Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376:2415-2426.
90. Johnson BE. Divide and conquer to treat lung cancer. N Engl J Med 2016;375:1892-1893.
91. Dong ZY, Zhong W, Zhang XC, et al. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin Cancer Res 2017;23: 3012-3024.
92. Lizotte PH, Ivanova EV, Awad MM, et al. Multiparametric profiling of non-small-cell lung cancers reveals distinct immunophenotypes. JCI Insight 2016;1:e89014.
93. Skoulidis F, Byers LA, Diao L, et al. Co-occurring genomic alterations define major subsets of KRASmutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 2015;5:860-877.
94. Koyama S, Akbay EA, Li YY, et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res 2016;76:999-1008.
95. Kadara H, Choi M, Zhang J, et al. Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical followup. Ann Oncol 2017;28:75-82.
96. Cabillic F, Bouet-Toussaint F, Toutirais O, et al. Interleukin-6 and vascular endothelial growth factor release by renal cell carcinoma cells impedes lymphocyte-dendritic cell cross-talk. Clin Exp Immunol 2006;146:518-523.
97. Figel AM, Brech D, Prinz PU, et al. Human renal cell carcinoma induces a dendritic cell subset that uses T-cell crosstalk for tumor-permissive milieu alterations. Am J Pathol 2011;179:436-451.
98. Giraldo NA, Becht E, Pages F, et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res 2015;21:3031-3040.
99. Remark R, Alifano M, Cremer I, et al. Characteristics and clinical impacts of the immune environments in colorectal and renal cell carcinoma lung metastases: influence of tumor origin. Clin Cancer Res 2013;19: 4079-4091.
100. Sautes-Fridman C, Lawand M, Giraldo NA, et al. Tertiary lymphoid structures in cancers: prognostic value, regulation, and manipulation for therapeutic intervention. Front Immunol 2016;7:407.
101. Nakano O, Sato M, Naito Y, et al. Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 2001;61:5132-5136.
102. Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res 2007;13:1757-1761.
103. Giraldo NA, Becht E, Vano Y, et al. Tumor-infiltrating and peripheral blood t-cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma. Clin Cancer Res 2017;23:4416-4428.
104. Kondo T, Nakazawa H, Ito F, et al. Favorable prognosis of renal cell carcinoma with increased expression of chemokines associated with a Th1- type immune response. Cancer Sci 2006;97:780-786.
105. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA 2004;101: 17174-17179.
106. Shin SJ, Jeon YK, Kim PJ, et al. Clinicopathologic analysis of PD-L1 and PD-L2 expression in renal cell carcinoma: association with oncogenic proteins status. Ann Surg Oncol 2016;23:694-702.
107. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003;21:3127-3132.
108. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol 2014;192:5451-5458.
109. 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;366:2443-2454.
110. 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: 2455-2465.
111. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol 2015;33: 1430-1437.
112. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-1813.
113. McDermott DF, Sosman JA, Sznol M, et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol 2016;34:833-842.
114. Faraj SF, Munari E, Guner G, et al. Assessment of tumoral PD-L1 expression and intratumoral CD8+ T cells in urothelial carcinoma. Urology 2015;85: 703e1-6.
115. Winerdal ME, Marits P, Winerdal M, et al. FOXP3 and survival in urinary bladder cancer. BJU Int 2011;108: 1672-1678.
116. Baras AS, Drake C, Liu JJ, et al. The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder. Oncoimmunology 2016;5: e1134412.
117. Boorjian SA, Sheinin Y, Crispen PL, et al. T-cell coregulatory molecule expression in urothelial cell carcinoma: clinicopathologic correlations and association with survival. Clin Cancer Res 2008;14: 4800-4808.
118. Xylinas E, Robinson BD, Kluth LA, et al. Association of T-cell co-regulatory protein expression with clinical outcomes following radical cystectomy for urothelial carcinoma of the bladder. Eur J Surg Oncol 2014;40:121-127.
119. Nakanishi J, Wada Y, Matsumoto K, et al. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 2007;56:1173-1182.
120. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer 2007;109:1499-1505.
121. Wang Y, Zhuang Q, Zhou S, et al. Costimulatory molecule B7-H1 on the immune escape of bladder cancer and its clinical significance. J Huazhong Univ Sci Technol Med Sci 2009;29:77-79.
122. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015;14:847-856.
123. Herr HW, Schwalb DM, Zhang ZF, et al. Intravesical bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J Clin Oncol 1995;13:1404-1408.
124. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti- PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515:558-562.
125. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016;387:1909-1920.
126. Malm IJ, Bruno TC, Fu J, et al. Expression profile and in vitro blockade of programmed death-1 in human papillomavirus-negative head and neck squamous cell carcinoma. Head Neck 2015;37:1088-1095.
127. Steidl C, Telenius A, Shah SP, et al. Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood 2010;116:418-427.
128. Bentz M, Barth TF, Bruderlein S, et al. Gain of chromosome arm 9p is characteristic of primary mediastinal B-cell lymphoma (MBL): comprehensive molecular cytogenetic analysis and presentation of a novel MBL cell line. Genes Chromosomes Cancer 2001;30:393-401.
129. Shi M, Roemer MG, Chapuy B, et al. 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 2014;38: 1715-1723.
130. Chapuy B, Roemer MG, Stewart C, et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 2016;127: 869-881.
131. Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 2013;19:3462-3473.
132. Roemer MG, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 genetic alterations define classical hodgkin lymphoma and predict outcome. J Clin Oncol 2016;34:2690-2697.
133. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015;372: 311-319.
134. Armand P, Shipp MA, Ribrag V, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol 2016;34: 3733-3739.
135. Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol 2016;34:2698-2704.
136. Westra WH, Taube JM, Poeta ML, et al. Inverse relationship between human papillomavirus-16 infection and disruptive p53 gene mutations in squamous cell carcinoma of the head and neck. Clin Cancer Res 2008;14:366-369.
137. Kim HS, Lee JY, Lim SH, et al. Association between PD-L1 and HPV status and the prognostic value of PDL1 in oropharyngeal squamous cell carcinoma. Cancer Res Treat 2016;48:527-536.
138. Bauml J, Seiwert TY, Pfister DG, et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol 2017;35:1542-1549.
139. Xie X, O'Neill W, Pan Q. Immunotherapy for head and neck cancer: the future of treatment? Expert Opin Biol Ther 2017;17:1-8.
140. Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res 2013;73:1733-1741.
141. Feldman R, Gatalica Z, Knezetic J, et al. Molecular profiling of head and neck squamous cell carcinoma. Head Neck 2016;38(Suppl 1):E1625-38.
142. Chow LQ, Haddad R, Gupta S, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol 2016;34:3838-3845.
143. Ferris RL, Blumenschein G Jr., Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856-1867.
144. Yearley JH, Gibson C, Yu N, et al. PD-L2 expression in human tumors: relevance to anti-PD-1 therapy in cancer. Clin Can Res 2017;23:3158-3167.
145. Lechner A, Schlosser H, Rothschild SI, et al. Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma. Oncotarget 2017;8: 44418-44433.
146. Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counterinhibitory checkpoints. Cancer Discov 2015;5:43-51.
147. Galon J, Angell HK, Bedognetti D, et al. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 2013;39:11-26.
148. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7-30.
149. Cimino-Mathews A, Foote JB, Emens LA. Immune targeting in breast cancer. Oncology (Williston Park) 2015;29:375-385.
150. Thompson E, Taube JM, Elwood H, et al. The immune microenvironment of breast ductal carcinoma in situ. Mod Pathol 2016;29:249-258.
151. Savas P, Salgado R, Denkert C, et al. Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat Rev Clin Oncol 2016;13:228-241.
152. Burugu S, Asleh-Aburaya K, Nielsen TO. Immune infiltrates in the breast cancer microenvironment: detection, characterization and clinical implication. Breast Cancer 2017;24:3-15.
153. Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 2015;26:259-271.
154. Moore OS Jr., Foote FW Jr. The relatively favorable prognosis of medullary carcinoma of the breast. Cancer 1949;2:635-642.
155. Ladoire S, Mignot G, Dabakuyo S, et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol 2011;224: 389-400.
156. Thompson E, Taube JM, Kendrick-Asch RJ, et al. PDL1 expression and the immune microenvironment in primary invasive lobular carcinomas of the breast. Mod Pathol 2017;30:1551-1560.
157. Li X, Li M, Lian Z, et al. Prognostic role of programmed death ligand-1 expression in breast cancer: a systematic review and meta-analysis. Target Oncol 2016;11:753-761.
158. Kroemer G, Galluzzi L, Kepp O, et al. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013;31:51-72.
159. Nanda R, Liu Minetta C, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2. J Clin Oncol 2017;35:506.
160. Lau J, Cheung J, Navarro A, et al. Tumour and host cell PD-L1 is required to mediate suppression of antitumour immunity in mice. Nat Commun 2017;8: 14572.
161. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated with anti-programmed death-1/ programmed death ligand 1 therapy. J Clin Oncol 2017;35:709-717.
162. Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:1749-1755.
163. Curry JL, Tetzlaff MT, Nagarajan P, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol 2017;44: 158-176.
164. Chen JH, Pezhouh MK, Lauwers GY, et al. Histopathologic features of colitis due to immunotherapy with anti-PD-1 antibodies. Am J Surg Pathol 2017;41: 643-654.
165. Kaunitz G, Loss M, Rizvi H, et al. Cutaneous eruptions in patients receiving immune checkpoint blockade: clinicopathologic analysis of the non-lichenoid histologic pattern. Am J Surg Pathol 2017;41:1381-1389.