The immune response in cancer: from immunology to pathology to immunotherapy

Virchows Archiv

Volumn 467, Issue 2, 2015, Pages 127-135

  Giraldo, Nicolas A ^a,b   Becht, Etienne ^a   Vano, Yann ^a   Sautès Fridman, Catherine ^a   Fridman, Wolf H ^a  

^a CENTRE DE RECHERCHE DES CORDELIERS   (France)

^b UNIVERSIDAD DE LOS ANDES   (Colombia)

Author keywords

Immunotherapies; Inflammation; Prognosis; Tumor microenvironment

Indexed keywords

CYTOKINE;

BLADDER CANCER; CANCER GROWTH; CANCER IMMUNOLOGY; CANCER IMMUNOTHERAPY; CANCER PROGNOSIS; CELLULAR IMMUNITY; CYTOKINE RESPONSE; HISTOPATHOLOGY; HODGKIN DISEASE; HUMAN; IMMUNE RESPONSE; INFLAMMATION; LUNG CANCER; LYMPHOCYTIC INFILTRATION; MELANOMA; METASTASIS; METASTATIC MELANOMA; NONHUMAN; PRIORITY JOURNAL; REVIEW; TUMOR ASSOCIATED LEUKOCYTE; TUMOR ESCAPE; TUMOR GROWTH; TUMOR IMMUNITY; TUMOR INVASION; TUMOR MICROENVIRONMENT; TUMOR VASCULARIZATION; ANIMAL; IMMUNOLOGY; IMMUNOTHERAPY; NEOPLASM; PROCEDURES;

ANIMALS; HUMANS; IMMUNOTHERAPY; NEOPLASMS; TUMOR ESCAPE; TUMOR MICROENVIRONMENT;

EID: 84938950486     PISSN: 09456317     EISSN: 14322307     Source Type: Journal    
DOI: 10.1007/s00428-015-1787-7     Document Type: Review

References (92)

1. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545
2. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444
3. Fridman WH, Pagès F, Sautès-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306
4. de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D, Plummer M (2012) Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 13:607–615
5. Salama NR, Hartung ML, Müller A (2013) Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori. Nat Rev Microbiol 11:385–399
6. Arzumanyan A, Reis HM, Feitelson MA (2013) Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 13:123–135
7. Rothenberg SM, Ellisen LM (2012) The molecular pathogenesis of head and neck squamous cell carcinoma. J Clin Invest 122:1951–1957
8. Castle PE, Hillier SL, Rabe LK, Hildesheim A, Herrero R, Bratti MC, Sherman ME, Burk RD, Rodriguez AC, Alfaro M, Hutchinson ML, Morales J, Schiffman M (2001) An association of cervical inflammation with high-grade cervical neoplasia in women infected with oncogenic human papilloma virus (HPV). Cancer Epidemiol Biomark 10:1021–1027
9. Houghton AM (2013) Mechanistic links between COPD and lung cancer. Nat Rev Cancer 13:233–245
10. Pennathur A, Gibson MK, Jobe BA, Luketich JD (2013) Oesophageal carcinoma. Lancet 281:400–412
11. Dyson JK, Rutter MD (2012) Colorectal cancer in inflammatory bowel disease: what is the real magnitude of the risk? World J Gastroenterol 18:3839–3848
12. Pinho AV, Chantrill L, Rooman I (2014) Chronic pancreatitis: a path to pancreatic cancer. Cancer Lett 345:203–209
13. Jayson GC, Kohn EC, Kitchener HC, Ledermann JA (2014) Ovarian cancer. Lancet 384:1376–1388
14. Chia WK, Ali R, Toh HC (2012) Aspirin as adjuvant therapy for colorectal cancer–reinterpreting paradigms. Nat Rev Clin Oncol 9:561–570
15. Gus-Brautbar Y, Johnson D, Zhang L, Sun H, Wang P, Zhang S, Zhang L, Chen YH (2012) The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras. Mol Cell 45:610–618
16. Sun B, Karin M (2014) The therapeutic value of targeting inflammation in gastrointestinal cancers. Trends Pharmacol Sci 35:349–357
17. Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ (2000) Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 60:184–190
18. Shuman-Moss LA, Jensen-Taubman S, Stetler-Stevenson WG (2012) Matrix metalloproteinases: changing roles in tumor progression and metastasis. Am J Pathol 181:1895–1899
19. Xue H, Lin B, Ni P, Xu H (2010) Huang G Interleukin-1B and interleukin-1 RN polymorphisms and gastric carcinoma risk: a meta-analysis. J Gastroenterol Hepatol 25:1604–1617
20. Haghnegahdar H, Du J, Wang D, Strieter RM, Burdick MD, Nanney LB, Cardwell N, Luan J, Shattuck-Brandt R, Richmond A (2000) The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma. J Leukoc Biol 67:53–62
21. Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4:540–550
22. Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51
23. Hoption-Cann SA, van Netten JP, van Netten C, Glover DW (2002) Spontaneous regression: a hidden treasure buried in time. Med Hypotheses 58:115–119
24. Bower M, Palmieri C, Dhillon T (2006) AIDS-related malignancies: changing epidemiology and the impact of highly active antiretroviral therapy. Curr Opin Infect Dis 19:14–19
25. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964
26. Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen YS, Shea LK, Hundal J, Wendl MC, Demeter R, Wylie T, Allison JP, Smyth MJ, Old LJ, Mardis ER, Schreiber RD (2012) Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482:400–404
27. Lennerz V, Fatho M, Gentilini C, Frye RA, Lifke A, Ferel D, Wölfel C, Huber C, Wölfel T (2005) The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci U S A 102:16013–16018
28. Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N (2010) Colorectal cancer. Lancet 375:1030–1047
29. Restifo NP, Dudley ME, Rosenberg SA (2012) Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 12:269–281
30. Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H (1998) The central role of CD4(+) T cells in the antitumor immune response. J Exp Med 188:2357–2368
31. Dieu-Nosjean MC, Goc J, Giraldo NA, Sautès-Fridman C, Fridman WH (2014) Tertiary Lymphoid Structures in cancer and beyond. Trends Immunol 35:571–580
32. Mlecnik B, Tosolini M, Charoentong P, Kirilovsky A, Bindea G, Berger A, Camus M, Gillard M, Bruneval P, Fridman WH, Pagès F, Trajanoski Z, Galon J (2010) Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology 138:1429–1440
33. de Chaisemartin L, Goc J, Damotte D, Validire P, Magdeleinat P, Alifano M, Cremer I, Fridman WH, Sautès-Fridman C, Dieu-Nosjean MC (2011) Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer. Cancer Res 71:6391–6399
34. Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263–274
35. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450--461
36. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034
37. Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704
38. Giraldo NA, Becht E, Remark R, Damotte D, Sautès-Fridman C, Fridman WH (2014) The immune contexture of primary and metastatic human tumours. Curr Opin Immunol 27:8–15
39. Galon J, Angell HK, Bedognetti D, Marincola FM (2013) The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 39:11–26
40. Muris JJ, Meijer CJ, Cillessen SA, Vos W, Kummer JA, Bladergroen BA, Bogman MJ, MacKenzie MA, Jiwa NM, Siegenbeek van Heukelom LH, Ossenkoppele GJ, Oudejans JJ (2004) Prognostic significance of activated cytotoxic T-lymphocytes in primary nodal diffuse large B-cell lymphomas. Leukemia 18:589–596
41. Scott DW, Chan FC, Hong F, Rogic S, Tan KL, Meissner B, Ben-Neriah S, Boyle M, Kridel R, Telenius A, Woolcock BW, Farinha P, Fisher RI, Rimsza LM, Bartlett NL, Cheson BD, Shepherd LE, Advani RH, Connors JM, Kahl BS, Gordon LI, Horning SJ, Steidl C, Gascoyne RD (2013) Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. J Clin Oncol 31:692–700
42. Giraldo NA, Becht E, Pages F, Skliris GP, Verkarre V, Vano Y, Mejean A, Saint-Aubert N, Lacroix L, Natario I, Lupo A, Alifano M, Damotte D, Cazes A, Triebel F, Freeman GJ, Dieu-Nosjean MC, Oudard SM, Fridman WH, Sautes-Fridman C (2015) Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res. doi:10.1158/1078-0432.CCR-14-2926
43. Zlobec I, Karamitopoulou E, Terracciano L, Piscuoglio S, Iezzi G, Muraro MG, Spagnoli G, Baker K, Tzankov A, Lugli A (2010) TIA-1 cytotoxic granule-associated RNA binding protein improves the prognostic performance of CD8 in mismatch repair-proficient colorectal cancer. PLoS One 5, e14282
44. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N (2015) Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160:48–61
45. Goc J, Germain C, Vo-Bourgais TK, Lupo A, Klein C, Knockaert S, de Chaisemartin L, Ouakrim H, Becht E, Alifano M, Validire P, Remark R, Hammond SA, Cremer I, Damotte D, Fridman WH, Sautès-Fridman C, Dieu-Nosjean MC (2014) Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Clin Cancer Res 74:705–715
46. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, Rabbe N, Laurans L, Tartour E, de Chaisemartin L, Lebecque S, Fridman WH, Cadranel J (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26:4410–4417
47. Cipponi A, Mercier M, Seremet T, Baurain JF, Théate I, van den Oord J, Stas M, Boon T, Coulie PG, van Baren N (2012) Neogenesis of lymphoid structures and antibody responses occur in human melanoma metastases. Cancer Res 72:3997–4007
48. Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ, Rochaix P, Girard JP (2011) Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res 71:5678–5687
49. + follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest 123:2873–2892
50. Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, Lugli A, Zlobec I, Hartmann A, Bifulco C, Nagtegaal ID, Palmqvist R, Masucci GV, Botti G, Tatangelo F, Delrio P, Maio M, Laghi L, Grizzi F, Asslaber M, D’Arrigo C, Vidal-Vanaclocha F, Zavadova E, Chouchane L, Ohashi PS, Hafezi-Bakhtiari S, Wouters BG, Roehrl M, Nguyen L, Kawakami Y, Hazama S, Okuno K, Ogino S, Gibbs P, Waring P, Sato N, Torigoe T, Itoh K, Patel PS, Shukla SN, Wang Y, Kopetz S, Sinicrope FA, Scripcariu V, Ascierto PA, Marincola FM, Fox BA, Pages F (2013) Towards the introduction of the Immunoscore in the classification of malignant tumors. J Pathol 232:199–209
51. Stack EC, Wang C, Roman KA, Hoyt CC (2014) Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of Tyramide signal amplification, multispectral imaging and multiplex analysis. Methods 70:46–58
52. Taylor RC, Patel A, Panageas KS, Busam KJ, Brady MS (2007) Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. J Clin Oncol 25:869–875
53. Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, Saw RP, Thompson JF (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
54. Thomas NE, Busam KJ, From L, Kricker A, Armstrong BK, Anton-Culver H, Gruber SB, Gallagher RP, Zanetti R, Rosso S, Dwyer T, Venn A, Kanetsky PA, Groben PA, Hao H, Orlow I, Reiner AS, Luo L, Paine S, Ollila DW, Wilcox H, Begg CB, Berwick M (2013) Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J Clin Oncol 31:4252–4259
55. Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, Bruneval P, Trajanoski Z, Fridman WH, Pagès F, Galon J (2011) Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 29:610–618
56. Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666
57. Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Frederiksen T, Lafontaine L, Berger A, Bruneval P, Fridman WH, Becker C, Speicher MR, Trajanoski Z, Galon J (2013) Spatio-temporal dynamics of intratumoral cells reveal the immune landscape in human cancer. Immunity 39:782–795
58. + regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat 130:645–655
59. Liu S, Lachapelle J, Leung S, Gao D, Foulkes WD, Nielsen TO (2012) CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res 14:R48
60. Kowalczyk D, Skorupski W, Kwias Z, Nowak J (1997) Flow cytometric analysis of tumour-infiltrating lymphocytes in patients with renal cell carcinoma. Br J Urol 80:543–547
61. Becht E, Goc J, Germain C, Giraldo NA, Dieu-Nosjean MC, Sautès-Fridman C, Fridman WH (2014) Shaping of an effective immune microenvironment to and by cancer cells. Cancer Immunol Immunother 63:991–997
62. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, Ellis IO, Green AR (2011) Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 29:1949–1955
63. Baker K, Lachapelle J, Zlobec I, Bismar TA, Terracciano L, Foulkes WD (2011) Prognostic significance of CD8+ T lymphocytes in breast cancer depends upon botho estrogen receptor status and histological grade. Histopathology 58:1107–1116
64. Kim ST, Jeong H, Woo OH, Seo JH, Kim A, Lee ES, Shin SW, Kim YH, Kim JS, Park KH (2013) Tumor-infiltrating lymphocytes, tumor characteristics, and recurrence in patients with early breast cancer. Am J Clin Oncol 36:224–231
65. +cytotoxic lymphocyte is a favorable prognostic marker in node-negative breast cancer. PLoS One 17, e95475
66. Mori M, Ohtani H, Naito Y, Sagawa M, Sato M, Fujimura S, Nagura H (2000) Infiltration of CD8+ T cells in non-small cell lung cancer is associated with dedifferentiation of cancer cells, but not with prognosis. Tohoku J Exp Med 191:113–118
67. Wakabayashi O, Yamazaki K, Oizumi S, Hommura F, Kinoshita I, Ogura S, Dosaka-Akita H, Nishimura M (2003) CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers. Cancer Sci 94:1003–1009
68. Hiraoka K, Miyamoto M, Cho Y, Suzuoki M, Oshikiri T, Nakakubo Y, Itoh T, Ohbuchi T, Kondo S, Katoh H (2006) Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 94:275–280
69. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT (2008) Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 15:5220–5227
70. Ikeguchi M, Oi K, Hirooka Y, Kaibara N (2004) CD8+ lymphocyte infiltration and apoptosis in hepatocellular carcinoma. Eur J Surg Oncol 30:53–57
71. Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge T, Nakajima A, Hirohashi S (2007) FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res 13:902–911
72. Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, Kato K, Kurokawa T, Suzuoki M, Nakakubo Y, Hiraoka K, Itoh T, Morikawa T, Okushiba S, Kondo S, Katoh H (2004) CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 28:e26–e31
73. Tewari N, Zaitoun AM, Arora A, Madhusudan S, Ilyas M, Lobo DN (2013) The presence of tumour-associated lymphocytes confers a good prognosis in pancreatic ductal adenocarcinoma: an immunohistochemical study of tissue microarrays. BMC Cancer 24:436
74. Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, Suzuki Y, Shintaku I, Nagura H, Ohtani H (2001) Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 61:5132–5136
75. Zlobec I, Terracciano LM, Lugli A (2008) Local recurrence in mismatch repair-proficient colon cancer predicted by an infiltrative tumor border and lack of CD8+ tumor-infiltrating lymphocytes. Clin Cancer Res 14:3792–3797
76. Däster S,Eppenberger-Castori S,HirtC,Zlobec I, DelkoT, Nebiker CA, Soysal SD, Amicarella F, Iezzi G, Sconocchia G, Heberer M, Lugli A, Spagnoli GC, Kettelhack C, Terracciano L, Oertli D, von Holzen U, Tornillo L, Droeser RA (2014) High frequency of CD8 positive lymphocyte infiltration correlates with lack of lymph node involvement in early rectal cancer. Dis Markers 2014: 792183
77. Koelzer VH, Dawson H,Andersson E, Karamitopoulou E,Masucci GV, Lugli A, Zlobec I (2015) Active immunosurveillance in the tumor microenvironment of colorectal cancer isassociated with low frequency tumor budding and improved outcome. Transl Res. doi:10.1016/j.trsl.2015.02.008
78. Rosenberg SA (2014) IL-2: the first effective immunotherapy for human cancer. J Immunol 192:5451–5458
79. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski 660 RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, 661 Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson 662 JA, Kim ST, Chen I, Huang X, Figlin RA (2009) Overall survival 663 and updated results for sunitinib compared with interferon alfa in 664 patients with metastatic renal cell carcinoma. J Clin Oncol 27: 665 3584–3590
80. Finke JH, Rayman PA, Ko JS, Bradley JM, Gendler SJ, Cohen PA (2013) Modification of the tumor microenvironment as a novel target of renal cell carcinoma therapeutics. Cancer J19:353–364
81. Speiser DE, Utzschneider DT, Oberle SG, Münz C, Romero P, Zehn D (2014) T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? Nat Rev Immunol 14:768–774
82. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723
83. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369:134–144
84. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 26:2443–2454
85. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465
86. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ (2015) Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol 33:1430--1437
87. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311–319
88. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL, Shen X, Boyd Z, Hegde PS, Chen DS, Vogelzang NJ (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558–562
89. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571
90. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20:5064–5074
91. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563–567
92. Shin DS, Ribas A (2015) The evolution of checkpoint blockade as a cancer therapy: what’s here, what’s next? Curr Opin Immunol 33C:23–35