PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations

Science Translational Medicine

Volumn 8, Issue 328, 2016, Pages

  Zou, Weiping ^a   Wolchok, Jedd D ^b   Chen, Lieping ^c  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^b MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^c YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINO N (3 CHLORO 4 FLUOROPHENYL) N' HYDROXY 1,2,5 OXADIAZOLE 3 CARBOXIMIDAMIDE; ATEZOLIZUMAB; BMS 936559; CD134 ANTIGEN; CD137 ANTIGEN; CD40 ANTIGEN; CD40 LIGAND; CP 870893; CYCLOOXYGENASE 2; DACETUZUMAB; IMATINIB; IPILIMUMAB; LUCATUMUMAB; NIVOLUMAB; OX40 LIGAND; PEMBROLIZUMAB; PIDILIZUMAB; PROGRAMMED DEATH 1 LIGAND 1; PROGRAMMED DEATH 1 RECEPTOR; SUNITINIB; TALIMOGENE LAHERPAREPVEC; TUMOR NECROSIS FACTOR; TUMOR MARKER;

ADOPTIVE IMMUNOTHERAPY; ANTIGEN PRESENTATION; ARTICLE; BLADDER CANCER; BREAST CANCER; CANCER CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CANCER RADIOTHERAPY; CANCER THERAPY; CASTRATION RESISTANT PROSTATE CANCER; CELL METABOLISM; COLORECTAL CANCER; DRUG RESPONSE; DRUG TARGETING; DUODENUM CANCER; EPIGENETICS; FOLLICULAR LYMPHOMA; GENE MUTATION; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HEMATOLOGIC MALIGNANCY; HUMAN; IMMUNE RESPONSE; INNATE IMMUNITY; KIDNEY CARCINOMA; LARGE CELL LYMPHOMA; MELANOMA; MICROFLORA; NON SMALL CELL LUNG CANCER; NONHUMAN; OVARY CANCER; PANCREAS CANCER; PANCREATICODUODENAL CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN EXPRESSION; SARCOMA; SIGNAL TRANSDUCTION; SOMATIC MUTATION; STOMACH CANCER; T LYMPHOCYTE; TH1 CELL; TUMOR MICROENVIRONMENT; UTERUS CANCER; ANIMAL; METABOLISM; NEOPLASMS;

ANIMALS; ANTIGENS, CD274; BIOMARKERS, TUMOR; HUMANS; MICROBIOTA; NEOPLASMS; PROGRAMMED CELL DEATH 1 RECEPTOR; SIGNAL TRANSDUCTION;

EID: 84959529731     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aad7118     Document Type: Article

References (177)

1. W. Zou, Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 5, 263-274 (2005).
2. D. M. Pardoll, The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252-264 (2012).
3. T. F. Gajewski, H. Schreiber, Y.-X. Fu, Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014-1022 (2013).
4. T. J. Curiel, G. Coukos, L. Zou, X. Alvarez, P. Cheng, P. Mottram, M. Evdemon-Hogan, J. R. Conejo-Garcia, L. Zhang, M. Burow, Y. Zhu, S. Wei, I. Kryczek, B. Daniel, A. Gordon, L. Myers, A. Lackner, M. L. Disis, K. L. Knutson, L. Chen, W. Zou, Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942-949 (2004).
5. T. J. Curiel, S. Wei, H.Dong, X. Alvarez, P. Cheng, P. Mottram, R. Krzysiek, K. L. Knutson, B.Daniel, M. C. Zimmermann, O. David, M. Burow, A. Gordon, N. Dhurandhar, L. Myers, R. Berggren, A. Hemminki, R. D. Alvarez, D. Emilie, D. T. Curiel, L. Chen, W. Zou, Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat. Med. 9, 562-567 (2003).
6. I. Kryczek, L. Zou, P. Rodriguez, G. Zhu, S. Wei, P. Mottram, M. Brumlik, P. Cheng, T. Curiel, L. Myers, A. Lackner, X. Alvarez, A. Ochoa, L. Chen, W. Zou, B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203, 871-881 (2006).
7. T. X. Cui, I. Kryczek, L. Zhao, E. Zhao, R. Kuick, M. H. Roh, L. Vatan, W. Szeliga, Y. Mao, D. G. Thomas, J. Kotarski, R. Tarkowski, M. Wicha, K. Cho, T. Giordano, R. Liu, W. Zou, Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 39, 611-621 (2013).
8. L. Zhang, J. R. Conejo-Garcia, D. Katsaros, P. A. Gimotty, M. Massobrio, G. Regnani, A. Makrigiannakis, H. Gray, K. Schlienger, M. N. Liebman, S. C. Rubin, G. Coukos, Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203-213 (2003).
9. F. Pagès, A. Berger, M. Camus, F. Sanchez-Cabo, A. Costes, R. Molidor, B. Mlecnik, A. Kirilovsky, M. Nilsson, D. Damotte, T. Meatchi, P. Bruneval, P.-H. Cugnenc, Z. Trajanoski, W.-H. Fridman, J. Galon, Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353, 2654-2666 (2005).
10. J. Galon, A. Costes, F. Sanchez-Cabo, A. Kirilovsky, B. Mlecnik, C. Lagorce-Pagès, M. Tosolini, M. Camus, A. Berger, P. Wind, F. Zinzindohoué, P. Bruneval, P.-H. Cugnenc, Z. Trajanoski, W.-H. Fridman, F. Pagès, Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960-1964 (2006).
11. I. Kryczek, E. Zhao, Y. Liu, Y. Wang, L. Vatan, W. Szeliga, J. Moyer, A. Klimczak, A. Lange, W. Zou, Human TH17 cells are long-lived effector memory cells. Sci. Transl. Med. 3, 104ra100 (2011).
12. I. Kryczek, Y. Lin, N. Nagarsheth, D. Peng, L. Zhao, E. Zhao, L. Vatan, W. Szeliga, Y. Dou, S. Owens, W. Zgodzinski, M. Majewski, G. Wallner, J. Fang, E. Huang, W. Zou, IL-22+CD4+ T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity 40, 772-784 (2014).
13. E. Zhao, T. Maj, I. Kryczek, W. Li, K. Wu, L. Zhao, S. Wei, J. Crespo, S.Wan, L. Vatan, W. Szeliga, I. Shao, Y. Wang, Y. Liu, S. Varambally, A. M. Chinnaiyan, T. H. Welling, V. Marquez, J. Kotarski, H. Wang, Z. Wang, Y. Zhang, R. Liu, G. Wang, W. Zou, Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat. Immunol. 17, 95-103 (2016).
14. W. Zou, L. Chen, Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol. 8, 467-477 (2008).
15. L. Chen, X. Han, Anti-PD-1/PD-L1 therapy of human cancer: Past, present, and future. J. Clin. Invest. 125, 3384-3391 (2015).
16. H. Dong, G. Zhu, K. Tamada, L. Chen, B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med. 5, 1365-1369 (1999).
17. H. Dong, S. E. Strome, D. R. Salomao, H. Tamura, F.Hirano, D. B. Flies, P. C. Roche, J. Lu, G. Zhu, K. Tamada, V. A. Lennon, E. Celis, L. Chen, Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat. Med. 8, 793-800 (2002).
18. G. J. Freeman, A. J. Long, Y. Iwai, K. Bourque, T. Chernova, H. Nishimura, L. J. Fitz, N. Malenkovich, T. Okazaki, M. C. Byrne, H. F. Horton, L. Fouser, L. Carter, V. Ling, M. R. Bowman, B. M. Carreno, M. Collins, C. R. Wood, T. Honjo, 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 (2000).
19. R. M. Wong, R. R. Scotland, R. L. Lau, C. Wang, A. J. Korman, W. M. Kast, J. S. Weber, Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int. Immunol. 19, 1223-1234 (2007).
20. K. Wu, I. Kryczek, L. Chen, W. Zou, T. H. Welling, Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res. 69, 8067-8075 (2009).
21. M. Ahmadzadeh, L. A. Johnson, B. Heemskerk, J. R. Wunderlich, M. E. Dudley, D. E. White, S. A. Rosenberg, Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114, 1537-1544 (2009).
22. J. Fourcade, Z. Sun, M. Benallaoua, P. Guillaume, I. F. Luescher, C. Sander, J. M. Kirkwood, V. Kuchroo, H. M. Zarour, Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175-2186 (2010).
23. J. Matsuzaki, S. Gnjatic, P. Mhawech-Fauceglia, A. Beck, A. Miller, T. Tsuji, C. Eppolito, F. Qian, S. Lele, P. Shrikant, L. J. Old, K. Odunsi, Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc. Natl. Acad. Sci. U.S.A. 107, 7875-7880 (2010).
24. I. Perrot, D. Blanchard, N. Freymond, S. Isaac, B. Guibert, Y. Pachéco, S. Lebecque, Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. J. Immunol. 178, 2763-2769 (2007).
25. D.-M. Kuang, Q. Zhao, C. Peng, J. Xu, J.-P. Zhang, C. Wu, L. Zheng, Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327-1337 (2009).
26. M. R. Nazareth, L. Broderick, M. R. Simpson-Abelson, R. J. Kelleher Jr., S. J. Yokota, R. B. Bankert, Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells. J. Immunol. 178, 5552-5562 (2007).
27. R. H. Thompson, M. D. Gillett, J. C. Cheville, C. M. Lohse, H. Dong, W. S. Webster, K. G. Krejci, J. R. Lobo, S. Sengupta, L. Chen, H. Zincke, M. L. Blute, S. E. Strome, B. C. Leibovich, E. D. Kwon, Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc. Natl. Acad. Sci. U.S.A. 101, 17174-17179 (2004).
28. H. Ghebeh, S. Mohammed, A. Al-Omair, A. Qattant, C. Lehe, G. Al-Qudaihi, N. Elkum, M. Alshabanah, S. Bin Amer, A. Tulbah, D. Ajarim, T. Al-Tweigeri, S. Dermime, The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: Correlation with important high-risk prognostic factors. Neoplasia 8, 190-198 (2006).
29. J. A. Brown, D. M. Dorfman, F.-R. Ma, E. L. Sullivan, O. Munoz, C. R. Wood, E. A. Greenfield, G. J. Freeman, Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol. 170, 1257-1266 (2003).
30. I. Kryczek, S. Wei, W. Gong, X. Shu, W. Szeliga, L. Vatan, L. Chen, G. Wang, W. Zou, Cutting edge: IFN-g enables APC to promote memory Th17 and abate Th1 cell development. J. Immunol. 181, 5842-5846 (2008).
31. J. M. Taube, R. A. Anders, G. D. Young, H. Xu, R. Sharma, T. L. McMiller, S. Chen, A. P. Klein, D. M. Pardoll, S. L. Topalian, L. Chen, Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 4, 127ra37 (2012).
32. S. Spranger, R. M. Spaapen, Y. Zha, J. Williams, Y. Meng, T. T. Ha, T. F. Gajewski, Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl. Med. 5, 200ra116 (2013).
33. S. L. Topalian, C. G. Drake, D. M. Pardoll, Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell 27, 450-461 (2015).
34. A. T. Parsa, J. S.Waldron, A. Panner, C. A. Crane, I. F. Parney, J. J. Barry, K. E. Cachola, J. C. Murray, T. Tihan, M. C. Jensen, P. S. Mischel, D. Stokoe, R. O. Pieper, Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med. 13, 84-88 (2007).
35. E. A. Mittendorf, A. V. Philips, F. Meric-Bernstam, N. Qiao, Y. Wu, S. Harrington, X. Su, Y. Wang, A. M. Gonzalez-Angulo, A. Akcakanat, A. Chawla, M. Curran, P. Hwu, P. Sharma, J. K. Litton, J. J. Molldrem, G. Alatrash, PD-L1 expression in triple-negative breast cancer. Cancer Immunol. Res. 2, 361-370 (2014).
36. M. Marzec, Q. Zhang, A. Goradia, P. N. Raghunath, X. Liu, M. Paessler, H. Y. Wang, M.Wysocka, M. Cheng, B. A. Ruggeri, M. A. Wasik, Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc. Natl. Acad. Sci. U.S.A. 105, 20852-20857 (2008).
37. Y. Agata, A. Kawasaki, H. Nishimura, Y. Ishida, T. Tsubata, H. Yagita, T. Honjo, Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765-772 (1996).
38. D. L. Barber, E. J. Wherry, D. Masopust, B. Zhu, J. P. Allison, A. H. Sharpe, G. J. Freeman, R. Ahmed, Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682-687 (2006).
39. C. L. Day, D. E. Kaufmann, P. Kiepiela, J. A. Brown, E. S. Moodley, S. Reddy, E. W. Mackey, J. D. Miller, A. J. Leslie, C. DePierres, Z. Mncube, J. Duraiswamy, B. Zhu, Q. Eichbaum, M. Altfeld, E. J. Wherry, H. M. Coovadia, P. J. R. Goulder, P. Klenerman, R. Ahmed, G. J. Freeman, B. D. Walker, PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350-354 (2006).
40. S. Kleffel, C. Posch, S. R. Barthel, H. Mueller, C. Schlapbach, E. Guenova, C. P. Elco, N. Lee, V. R. Juneja, Q. Zhan, C.G. Lian, R. Thomi, W. Hoetzenecker, A. Cozzio, R. Dummer, M. C. MihmJr., K. T. Flaherty, M. H. Frank, G. F. Murphy, A. H. Sharpe, T. S. Kupper, T. Schatton, Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162, 1242-1256 (2015).
41. J. M. Taube, A. Klein, J. R. Brahmer, H. Xu, X. Pan, J. H. Kim, L. Chen, D. M. Pardoll, S. L. Topalian, R. A. Anders, 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 (2014).
42. M. J. Butte, M. E. Keir, T. B. Phamduy, A. H. Sharpe, G. J. Freeman, Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27, 111-122 (2007).
43. J.-J. Park, R. Omiya, Y. Matsumura, Y. Sakoda, A. Kuramasu, M. M. Augustine, S. Yao, F. Tsushima, H. Narazaki, S. Anand, Y. Liu, S. E. Strome, L. Chen, K. Tamada, B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 116, 1291-1298 (2010).
44. H. Dong, S. E. Strome, E. L. Matteson, K. G. Moder, D. B. Flies, G. Zhu, H. Tamura, C. L. W. Driscoll, L. Chen, Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis. J. Clin. Invest. 111, 363-370 (2003).
45. T. Azuma, S. Yao, G. Zhu, A. S. Flies, S. J. Flies, L. Chen, B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood 111, 3635-3643 (2008).
46. Y. Xiao, S. Yu, B. Zhu, D. Bedoret, X. Bu, L. M. Francisco, P. Hua, J. S. Duke-Cohan, D. T. Umetsu, A. H. Sharpe, R. H. DeKruyff, G. J. Freeman, RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J. Exp. Med. 211, 943-959 (2014).
47. T. Powles, J. P. Eder, G. D. Fine, F. S. Braiteh, Y. Loriot, C. Cruz, J. Bellmunt, H. A. Burris, D. P. Petrylak, S.-l. Teng, X. Shen, Z. Boyd, P. S. Hegde, D. S. Chen, N. J. Vogelzang, MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558-562 (2014).
48. J. R. Brahmer, S. S. Tykodi, L. Q. M. Chow, W.-J. Hwu, S. L. Topalian, P. Hwu, C. G. Drake, L. H. Camacho, J. Kauh, K. Odunsi, H. C. Pitot, O. Hamid, S. Bhatia, R. Martins, K. Eaton, S. Chen, T. M. Salay, S. Alaparthy, J. F. Grosso, A. J. Korman, S. M. Parker, S. Agrawal, S. M. Goldberg, D. M. Pardoll, A. Gupta, J. M. Wigginton, Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455-2465 (2012).
49. R. S. Herbst, J.-C. Soria, M. Kowanetz, G. D. Fine, O. Hamid, M. S. Gordon, J. A. Sosman, D. F. McDermott, J. D. Powderly, S. N. Gettinger, H. E. K. Kohrt, L. Horn, D. P. Lawrence, S. Rost, M. Leabman, Y. Xiao, A. Mokatrin, H. Koeppen, P. S. Hegde, I. Mellman, D. S. Chen, F. S. Hodi, Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563-567 (2014).
50. J. R. Brahmer, C. G. Drake, I. Wollner, J. D. Powderly, J. Picus, W. H. Sharfman, E. Stankevich, A. Pons, T. M. Salay, T. L. McMiller, M. M. Gilson, C. Wang, M. Selby, J. M. Taube, R. Anders, L. Chen, A. J. Korman, D. M. Pardoll, I. Lowy, S. L. Topalian, Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167-3175 (2010).
51. S. L. Topalian, F. S. Hodi, J. R. Brahmer, S. N. Gettinger, D. C. Smith, D. F. McDermott, J. D. Powderly, R. D. Carvajal, J. A. Sosman, M. B. Atkins, P. D. Leming, D. R. Spigel, S. J. Antonia, L. Horn, C. G. Drake, D. M. Pardoll, L. Chen, W. H. Sharfman, R. A. Anders, J. M. Taube, T. L. McMiller, H. Xu, A. J. Korman, M. Jure-Kunkel, S. Agrawal, D. McDonald, G. D. Kollia, A. Gupta, J. M. Wigginton, M. Sznol, Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443-2454 (2012).
52. E. J. Lipson, W. H. Sharfman, C. G. Drake, I. Wollner, J. M. Taube, R. A. Anders, H. Xu, S. Yao, A. Pons, L. Chen, D. M. Pardoll, J. R. Brahmer, S. L. Topalian, Durable cancer regression offtreatment and effective reinduction therapy with an anti-PD-1 antibody. Clin. Cancer Res. 19, 462-468 (2013).
53. D. T. Le, J. N. Uram, H. Wang, B. R. Bartlett, H. Kemberling, A. D. Eyring, A. D. Skora, B. S. Luber, N. S. Azad, D. Laheru, B. Biedrzycki, R. C. Donehower, A. Zaheer, G. A. Fisher, T. S. Crocenzi, J. J. Lee, S. M. Duffy, R. M. Goldberg, A. De la Chapelle, M. Koshiji, F. Bhaijee, T. Huebner, R. H. Hruban, L. D. Wood, N. Cuka, D. M. Pardoll, N. Papadopoulos, K. W. Kinzler, S. Zhou, T. C. Cornish, J. M. Taube, R. A. Anders, J. R. Eshleman, B. Vogelstein, L. A. Diaz Jr., PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509-2520 (2015).
54. P. Armand, A. Nagler, E. A. Weller, S. M. Devine, D. E. Avigan, Y.-B. Chen, M. S. Kaminski, H. K. Holland, J. N. Winter, J. R. Mason, J. W. Fay, D. A. Rizzieri, C. M. Hosing, E. D. Ball, J. P. Uberti, H. M. Lazarus, M. Y. Mapara, S. A. Gregory, J. M. Timmerman, D. Andorsky, R. Or, E. K. Waller, R. Rotem-Yehudar, L. I. Gordon, Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: Results of an international phase II trial. J. Clin. Oncol. 31, 4199-4206 (2013).
55. J. R. Westin, F. Chu, M. Zhang, L. E. Fayad, L. W. Kwak, N. Fowler, J. Romaguera, F. Hagemeister, M. Fanale, F. Samaniego, L. Feng, V. Baladandayuthapani, Z. Wang, W. Ma, Y. Gao, M. Wallace, L. M. Vence, L. Radvanyi, T. Muzzafar, R. Rotem-Yehudar, R. E. Davis, S. S. Neelapu, Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: A single group, open-label, phase 2 trial. Lancet Oncol. 15, 69-77 (2014).
56. S. M. Ansell, A. M. Lesokhin, I. Borrello, A. Halwani, E. C. Scott, M. Gutierrez, S. J. Schuster, M. M. Millenson, D. Cattry, G. J. Freeman, S. J. Rodig, B. Chapuy, A. H. Ligon, L. Zhu, J. F. Grosso, S. Y. Kim, J. M. Timmerman, M. A. Shipp, P. Armand, PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311-319 (2015).
57. O. Hamid, C. Robert, A. Daud, F. S. Hodi, W.-J. Hwu, R. Kefford, J. D. Wolchok, P. Hersey, R. W. Joseph, J. S. Weber, R. Dronca, T. C. Gangadhar, A. Patnaik, H. Zarour, A. M. Joshua, K. Gergich, J. Elassaiss-Schaap, A. Algazi, C. Mateus, P. Boasberg, P. C. Tumeh, B. Chmielowski, S. W. Ebbinghaus, X. N. Li, S. P. Kang, A. Ribas, Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134-144 (2013).
58. J. D. Wolchok, H. Kluger, M. K. Callahan, M. A. Postow, N. A. Rizvi, A. M. Lesokhin, N. H. Segal, C. E. Ariyan, R.-A. Gordon, K. Reed, M.M. Burke, A. Caldwell, S. A. Kronenberg, B. U. Agunwamba, X. Zhang, I. Lowy, H. D. Inzunza, W. Feely, C. E. Horak, Q. Hong, A. J. Korman, J. M. Wigginton, A. Gupta, M. Sznol, Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122-133 (2013).
59. J. S. Weber, R. R. Kudchadkar, B. Yu, D. Gallenstein, C. E. Horak, H. D. Inzunza, X. Zhao, A. J. Martinez, W. Wang, G. Gibney, J. Kroeger, C. Eysmans, A. A. Sarnaik, Y. A. Chen, Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J. Clin. Oncol. 31, 4311-4318 (2013).
60. S. L. Topalian, M. Sznol, D. F. McDermott, H. M. Kluger, R. D. Carvajal, W. H. Sharfman, J. R. Brahmer, D. P. Lawrence, M. B. Atkins, J. D. Powderly, P. D. Leming, E. J. Lipson, I. Puzanov, D. C. Smith, J. M. Taube, J. M. Wigginton, G. D. Kollia, A. Gupta, D. M. Pardoll, J. A. Sosman, F. S. Hodi, Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020-1030 (2014).
61. C. Robert, A. Ribas, J. D. Wolchok, F. S. Hodi, O. Hamid, R. Kefford, J. S. Weber, A. M. Joshua, W.-J. Hwu, T. C. Gangadhar, A. Patnaik, R. Dronca, H. Zarour, R. W. Joseph, P. Boasberg, B. Chmielowski, C. Mateus, M. A. Postow, K. Gergich, J. Elassaiss-Schaap, X. N. Li, R. Iannone, S. W. Ebbinghaus, S. P. Kang, A. Daud, Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 384, 1109-1117 (2014).
62. C. Robert, J. Schachter, G. V. Long, A. Arance, J. J. Grob, L. Mortier, A. Daud, M. S. Carlino, C. McNeil, M. Lotem, J. Larkin, P. Lorigan, B. Neyns, C. U. Blank, O. Hamid, C. Mateus, R. Shapira-Frommer, M. Kosh, H. Zhou, N. Ibrahim, S. Ebbinghaus, A. Ribas; KEYNOTE-006 investigators, Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521-2532 (2015).
63. J. Larkin, V. Chiarion-Sileni, R. Gonzalez, J. J. Grob, C. L. Cowey, C. D. Lao, D. Schadendorf, R. Dummer, M. Smylie, P. Rutkowski, P. F. Ferrucci, A. Hill, J. Wagstaff, M. S. Carlino, J. B. Haanen, M.Maio, I. Marquez-Rodas, G. A. McArthur, P. A. Ascierto, G. V. Long, M. K. Callahan, M. A. Postow, K. Grossmann, M. Sznol, B. Dreno, L. Bastholt, A. Yang, L. M. Rollin, C. Horak, F. S. Hodi, J. D.Wolchok, Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23-34 (2015).
64. C. Robert, G. V. Long, B. Brady, C. Dutriaux, M. Maio, L. Mortier, J. C. Hassel, P. Rutkowski, C. McNeil, E. Kalinka-Warzocha, K. J. Savage, M. M. Hernberg, C. Lebbé, J. Charles, C. Mihalcioiu, V. Chiarion-Sileni, C. Mauch, F. Cognetti, A. Arance, H. Schmidt, D. Schadendorf, H. Gogas, L. Lundgren-Eriksson, C. Horak, B. Sharkey, I. M. Waxman, V. Atkinson, P. A. Ascierto, Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320-330 (2015).
65. J. S. Weber, S. P. D'Angelo, D. Minor, F. S. Hodi, R. Gutzmer, B. Neyns, C. Hoeller, N. I. Khushalani, W. H. Miller Jr., C. D. Lao, G. P. Linette, L. Thomas, P. Lorigan, K. F. Grossmann, J. C. Hassel, M. Maio, M. Sznol, P. A. Ascierto, P. Mohr, B. Chmielowski, A. Bryce, I. M. Svane, J.-J. Grob, A. M. Krackhardt, C. Horak, A. Lambert, A. S. Yang, J. Larkin, Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16, 375-384 (2015).
66. E. B. Garon, N. A. Rizvi, R. Hui, N. Leighl, A. S. Balmanoukian, J. P. Eder, A. Patnaik, C. Aggarwal, M. Gubens, L. Horn, E. Carcereny, M.-J. Ahn, E. Felip, J.-S. Lee, M. D. Hellmann, O. Hamid, J. W. Goldman, J.-C. Soria, M. Dolled-Filhart, R. Z. Rutledge, J. Zhang, J. K. Lunceford, R. Rangwala, G.M. Lubiniecki, C. Roach, K. Emancipator, L. Gandhi; KEYNOTE-001 Investigators, Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018-2028 (2015).
67. N. A. Rizvi, M. D. Hellmann, A. Snyder, P. Kvistborg, V. Makarov, J. J. Havel, W. Lee, J. Yuan, P. Wong, T. S. Ho, M. L. Miller, N. Rekhtman, A. L.Moreira, F. Ibrahim, C. Bruggeman, B. Gasmi, R. Zappasodi, Y.Maeda, C. Sander, E. B. Garon, T. Merghoub, J. D.Wolchok, T. N. Schumacher, T. A. Chan, Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124-128 (2015).
68. J. Brahmer, K. L. Reckamp, P. Baas, L. Crinò, W. E. E. Eberhardt, E. Poddubskaya, S. Antonia, A. Pluzanski, E. E. Vokes, E. Holgado, D. Waterhouse, N. Ready, J. Gainor, O. Arén Frontera, L. Havel, M. Steins, M. C. Garassino, J. G. Aerts, M. Domine, L. Paz-Ares, M. Reck, C. Baudelet, C. T. Harbison, B. Lestini, D. R. Spigel, Nivolumab versus docetaxel in advanced squamouscell non-small-cell lung cancer. N. Engl. J. Med. 373, 123-135 (2015).
69. S. N. Gettinger, L. Horn, L. Gandhi, D. R. Spigel, S. J. Antonia, N. A. Rizvi, J. D. Powderly, R. S. Heist, R. D. Carvajal, D. M. Jackman, L. V. Sequist, D. C. Smith, P. Leming, D. P. Carbone, M. C. Pinder-Schenck, S. L. Topalian, F. S. Hodi, J. A. Sosman, M. Sznol, D. F. McDermott, D. M. Pardoll, V. Sankar, C. M. Ahlers, M. Salvati, J. M. Wigginton, M. D. Hellmann, G. D. Kollia, A. K. Gupta, J. R. Brahmer, Overall survival and long-term safety of nivolumab (antiprogrammed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J. Clin. Oncol. 33, 2004-2012 (2015).
70. N. A. Rizvi, J. Mazières, D. Planchard, T. E. Stinchcombe, G. K. Dy, S. J. Antonia, L. Horn, H. Lena, E. Minenza, B. Mennecier, G. A. Otterson, L. T. Campos, D. R. Gandara, B. P. Levy, S. G. Nair, G. Zalcman, J. Wolf, P.-J. Souquet, E. Baldini, F. Cappuzzo, C. Chouaid, A. Dowlati, R. Sanborn, A. Lopez-Chavez, C. Grohe, R. M. Huber, C. T. Harbison, C. Baudelet, B. J. Lestini, S. S. Ramalingam, Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol. 16, 257-265 (2015).
71. D. F. McDermott, C. G. Drake, M. Sznol, T. K. Choueiri, J. D. Powderly, D. C. Smith, J. R. Brahmer, R. D. Carvajal, H. J. Hammers, I. Puzanov, F. S. Hodi, H. M. Kluger, S. L. Topalian, D. M. Pardoll, J. M. Wigginton, G. D. Kollia, A. Gupta, D. McDonald, V. Sankar, J. A. Sosman, M. B. Atkins, Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J. Clin. Oncol. 33, 2013-2020 (2015).
72. R. H. Thompson, S. M. Kuntz, B. C. Leibovich, H. Dong, C. M. Lohse, W. S. Webster, S. Sengupta, I. Frank, A. S. Parker, H. Zincke, M. L. Blute, T. J. Sebo, J. C. Cheville, E. D. Kwon, Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res. 66, 3381-3385 (2006).
73. Y. Ohigashi, M. Sho, Y. Yamada, Y. Tsurui, K. Hamada, N. Ikeda, T. Mizuno, R. Yoriki, H. Kashizuka, K. Yane, F. Tsushima, N. Otsuki, H. Yagita, M. Azuma, Y. Nakajima, Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin. Cancer Res. 11, 2947-2953 (2005).
74. C. Wu, Y. Zhu, J. Jiang, J. Zhao, X.-G. Zhang, N. Xu, Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 108, 19-24 (2006).
75. J. Hamanishi, M. Mandai, M. Iwasaki, T. Okazaki, Y. Tanaka, K. Yamaguchi, T. Higuchi, H. Yagi, K. Takakura, N. Minato, T. Honjo, S. Fujii, Programmed cell death 1 ligand 1 and tumorinfiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci. U.S.A. 104, 3360-3365 (2007).
76. M. A. Postow, J. Chesney, A. C. Pavlick, C. Robert, K. Grossmann, D. McDermott, G. P. Linette, N. Meyer, J. K. Giguere, S. S. Agarwala, M. Shaheen, M. S. Ernstoff, D. Minor, A. K. Salama, M. Taylor, P. A. Ott, L. M. Rollin, C. Horak, P. Gagnier, J. D. Wolchok, F. S. Hodi, Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006-2017 (2015).
77. R. L. Maute, S. R. Gordon, A. T. Mayer, M. N. McCracken, A. Natarajan, N. G. Ring, R. Kimura, J. M. Tsai, A. Manglik, A. C. Kruse, S. S. Gambhir, I. L. Weissman, A. M. Ring, Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging. Proc. Natl. Acad. Sci. U.S.A. 112, E6506-E6514 (2015).
78. H. M. Kluger, C. R. Zito, M. L. Barr, M. K. Baine, V. L. S. Chiang, M. Sznol, D. L. Rimm, L. Chen, L. B. Jilaveanu, Characterization of PD-L1 expression and associated T-cell infiltrates in metastatic melanoma samples from variable anatomic sites. Clin. Cancer Res. 21, 3052-3060 (2015).
79. M. DuPage, C. Mazumdar, L. M. Schmidt, A. F. Cheung, T. Jacks, Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482, 405-409 (2012).
80. H. Matsushita, M. D. Vesely, D. C. Koboldt, C. G. Rickert, R. Uppaluri, V. J. Magrini, C. D. Arthur, J. M. White, Y.-S. Chen, L. K. Shea, J. Hundal, M. C. Wendl, R. Demeter, T. Wylie, J. P. Allison, M. J. Smyth, L. J. Old, E. R. Mardis, R. D. Schreiber, Cancer exome analysis reveals a T-celldependent mechanism of cancer immunoediting. Nature 482, 400-404 (2012).
81. T. Schumacher, L. Bunse, S. Pusch, F. Sahm, B. Wiestler, J. Quandt, O. Menn, M. Osswald, I. Oezen, M. Ott, M. Keil, J. Balß, K. Rauschenbach, A. K. Grabowska, I. Vogler, J. Diekmann, N. Trautwein, S. B. Eichmüller, J. Okun, S. Stevanovic, A. B. Riemer, U. Sahin, M. A. Friese, P. Beckhove, A. Von Deimling, W. Wick, M. Platten, A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324-327 (2014).
82. S. Kreiter, M. Vormehr, N. Van de Roemer, M. Diken, M. Löwer, J. Diekmann, S. Boegel, B. Schrörs, F. Vascotto, J. C. Castle, A. D. Tadmor, S. P. Schoenberger, C. Huber, O. Türeci, U. Sahin, Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692-696 (2015).
83. E. Tran, S. Turcotte, A. Gros, P. F. Robbins, Y.-C. Lu, M. E. Dudley, J. R. Wunderlich, R. P. Somerville, K. Hogan, C. S. Hinrichs, M. R. Parkhurst, J. C. Yang, S. A. Rosenberg, Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641-645 (2014).
84. C. Linnemann, M.M. Van Buuren, L. Bies, E. M. E. Verdegaal, R. Schotte, J. J. A. Calis, S. Behjati, A. Velds, H. Hilkmann, D. e. Atmioui, M. Visser, M. R. Stratton, J. B. A. G. Haanen, H. Spits, S. H. Van der Burg, T. N. M. Schumacher, High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat. Med. 21, 81-85 (2015).
85. P. F. Robbins, Y.-C. Lu, M. El-Gamil, Y. F. Li, C. Gross, J. Gartner, J. C. Lin, J. K. Teer, P. Cliften, E. Tycksen, Y. Samuels, S. A. Rosenberg, Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747-752 (2013).
86. B. M. Carreno, V. Magrini, M. Becker-Hapak, S. Kaabinejadian, J. Hundal, A. A. Petti, A. Ly, W.-R. Lie, W. H. Hildebrand, E. R. Mardis, G. P. Linette, A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348, 803-808 (2015).
87. N. J. Llosa, M. Cruise, A. Tam, E. C. Wicks, E. M. Hechenbleikner, J. M. Taube, R. L. Blosser, H. Fan, H. Wang, B. S. Luber, M. Zhang, N. Papadopoulos, K. W. Kinzler, B. Vogelstein, C. L. Sears, R. A. Anders, D. M. Pardoll, F. Housseau, The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5, 43-51 (2015).
88. M. S. Rooney, S. A. Shukla, C. J. Wu, G. Getz, N. Hacohen, Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48-61 (2015).
89. M. M. Gubin, X. Zhang, H. Schuster, E. Caron, J. P. Ward, T. Noguchi, Y. Ivanova, J. Hundal, C. D. Arthur, W.-J. Krebber, G. E. Mulder, M. Toebes, M. D. Vesely, S. S. K. Lam, A. J. Korman, J. P. Allison, G. J. Freeman, A. H. Sharpe, E. L. Pearce, T. N. Schumacher, R. Aebersold, H.-G. Rammensee, C. J. M. Melief, E. R. Mardis, W. E. Gillanders, M. N. Artyomov, R. D. Schreiber, Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577-581 (2014).
90. L. B. Alexandrov, S. Nik-Zainal, D. C. Wedge, S. A. J. R. Aparicio, S. Behjati, A. V. Biankin, G. R. Bignell, N. Bolli, A. Borg, A.-L. Børresen-Dale, S. Boyault, B. Burkhardt, A. P. Butler, C. Caldas, H. R. Davies, C. Desmedt, R. Eils, J. E. Eyfjörd, J. A. Foekens, M. Greaves, F. Hosoda, B. Hutter, T. Ilicic, S. Imbeaud, M. Imielinsk, N. Jäger, D. T. W. Jones, D. Jones, S. Knappskog, M. Kool, S. R. Lakhani, C. López-Otín, S. Martin, N. C. Munshi, H. Nakamura, P. A. Northcott, M. Pajic, E. Papaemmanuil, A. Paradiso, J. V. Pearson, X. S. Puente, K. Raine, M. Ramakrishna, A. L. Richardson, J. Richter, P. Rosenstiel, M. Schlesner, T. N. Schumacher, P. N. Span, J. W. Teague, Y. Totoki, A. N. J. Tutt, R. Valdés-Mas, M. M. Van Buuren, L. Van 't Veer, A. Vincent-Salomon, N. Waddell, L. R. Yates; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium, ICGC PedBrain, J. Zucman-Rossi, P. A. Futreal, U. McDermott, P. Lichter, M. Meyerson, S. M. Grimmond, R. Siebert, E. Campo, T. Shibata, S. M. Pfister, P. J. Campbell, M. R. Stratton, Signatures of mutational processes in human cancer. Nature 500, 415-421 (2013).
91. T. N. Schumacher, R. D. Schreiber, Neoantigens in cancer immunotherapy. Science 348, 69-74 (2015).
92. I. Kryczek, M. Banerjee, P. Cheng, L. Vatan, W. Szeliga, S. Wei, E. Huang, E. Finlayson, D. Simeone, T. H. Welling, A. Chang, G. Coukos, R. Liu, W. Zou, Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114, 1141-1149 (2009).
93. S. Spranger, R. Bao, T. F. Gajewski, Melanoma-intrinsic b-catenin signalling prevents antitumour immunity. Nature 523, 231-235 (2015).
94. D. Peng, I. Kryczek, N. Nagarsheth, L. Zhao, S. Wei, W. Wang, Y. Sun, E. Zhao, L. Vatan, W. Szeliga, J. Kotarski, R. Tarkowski, Y. Dou, K. Cho, S. Hensley-Alford, A. Munkarah, R. Liu, W. Zou, Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249-253 (2015).
95. N Nagarsheth, D Peng, I Kryczek, K Wu, W Li, E Zhao, L Zhao, S Wei, T Frankel, L Vatan, W Szeliga, Y Dou, S Owens, V Marquez, K Tao, E Huang, G Wang, W Zou, PRC2 epigenetically silences Th1-type chemokines to suppress effector T cell trafficking in colon cancer. Cancer Res. 76, 275-282 2016.
96. W. Timp, A. P. Feinberg, Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat. Rev. Cancer 13, 497-510 (2013).
97. P. C. Tumeh, C. L. Harview, J. H. Yearley, I. P. Shintaku, E. J. M. Taylor, L. Robert, B. Chmielowski, M. Spasic, G. Henry, V. Ciobanu, A. N. West, M. Carmona, C. Kivork, E. Seja, G. Cherry, A. J. Gutierrez, T. R. Grogan, C. Mateus, G. Tomasic, J. A. Glaspy, R. O. Emerson, H. Robins, R. H. Pierce, D. A. Elashoff, C. Robert, A. Ribas, PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568-571 (2014).
98. S. Viaud, F. Saccheri, G. Mignot, T. Yamazaki, R. Daillère, D. Hannani, D. P. Enot, C. Pfirschke, C. Engblom, M. J. Pittet, A. Schlitzer, F. Ginhoux, L. Apetoh, E. Chachaty, P.-L. Woerther, G. Eberl, M. Bérard, C. Ecobichon, D. Clermont, C. Bizet, V. Gaboriau-Routhiau, N. Cerf-Bensussan, P.Opolon, N. Yessaad, E. Vivier, B. Ryffel, C.O. Elson, J. Doré, G. Kroemer, P. Lepage, I. G. Boneca, F. Ghiringhelli, L. Zitvogel, The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971-976 (2013).
99. N. Iida, A. Dzutsev, C. A. Stewart, L. Smith, N. Bouladoux, R. A. Weingarten, D. A. Molina, R. Salcedo, T. Back, S. Cramer, R.-M. Dai, H. Kiu, M. Cardone, S. Naik, A. K. Patri, E. Wang, F. M. Marincola, K. M. Frank, Y. Belkaid, G. Trinchieri, R. S. Goldszmid, Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967-970 (2013).
100. A. Sivan, L. Corrales, N. Hubert, J. B. Williams, K. Aquino-Michaels, Z. M. Earley, F. W. Benyamin, Y. M. Lei, B. Jabri, M.-L. Alegre, E. B. Chang, T. F. Gajewski, Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084-1089 (2015).
101. M. Vétizou, J. M. Pitt, R. Daillère, P. Lepage, N. Waldschmitt, C. Flament, S. Rusakiewicz, B. Routy, M. P. Roberti, C. P. M. Duong, V. Poirier-Colame, A. Roux, S. Becharef, S. Formenti, E. Golden, S. Cording, G. Eberl, A. Schlitzer, F. Ginhoux, S. Mani, T. Yamazaki, N. Jacquelot, D. P. Enot, M. Bérard, J. Nigou, P. Opolon, A. Eggermont, P.-L. Woerther, E. Chachaty, N. Chaput, C. Robert, C. Mateus, G. Kroemer, D. Raoult, I. G. Boneca, F. Carbonnel, M. Chamaillard, L. Zitvogel, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079-1084 (2015).
102. V. Velcheti, K. A. Schalper, D. E. Carvajal, V. K. Anagnostou, K. N. Syrigos, M. Sznol, R. S. Herbst, S. N. Gettinger, L. Chen, D. L. Rimm, Programmed death ligand-1 expression in non-small cell lung cancer. Lab. Invest. 94, 107-116 (2014).
103. J. Tan, X. Yang, L. Zhuang, X. Jiang, W. Chen, P. L. Lee, R. K. Karuturi, P. B. O. Tan, E. T. Liu, Q. Yu, Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 21, 1050-1063 (2007).
104. M. T. McCabe, H. M. Ott, G. Ganji, S. Korenchuk, C. Thompson, G. S. Van Aller, Y. Liu, A. P. Graves, A. Della Pietra III, E. Diaz, L. V. LaFrance, M. Mellinger, C. Duquenne, X. Tian, R. G. Kruger, C. F. McHugh, M. Brandt, W. H. Miller, D. Dhanak, S. K. Verma, P. J. Tummino, C. L. Creasy, EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108-112 (2012).
105. H. Li, K. B. Chiappinelli, A. A. Guzzetta, H. Easwaran, R.-W. C. Yen, R. Vatapalli, M. J. Topper, J. Luo, R. M. Connolly, N. S. Azad, V. Stearns, D.M. Pardoll, N. Davidson, P. A. Jones, D. J. Slamon, S. B. Baylin, C. A. Zahnow, N. Ahuja, Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 5, 587-598 (2014).
106. J. Wrangle, W. Wang, A. Koch, H. Easwaran, H. P. Mohammad, X. Pan, F. Vendetti, W. VanCriekinge, T. DeMeyer, Z. Du, P. Parsana, K. Rodgers, R.-W. Yen, C. A. Zahnow, J. M. Taube, J. R. Brahmer, S. S. Tykodi, K. Easton, R. D. Carvajal, P. A. Jones, P. W. Laird, D. J. Weisenberger, S. Tsai, R. A. Juergens, S. L. Topalian, C. M. Rudin, M. V. Brock, D. Pardoll, S. B. Baylin, Alterations of immune response of non-small cell lung cancer with azacytidine. Oncotarget 4, 2067-2079 (2013).
107. A. Woloszynska-Read, P. Mhawech-Fauceglia, J. Yu, K. Odunsi, A. R. Karpf, Intertumor and intratumor NY-ESO-1 expression heterogeneity is associated with promoter-specific and global DNA methylation status in ovarian cancer. Clin. Cancer Res. 14, 3283-3290 (2008).
108. L. Wang, Z. Amoozgar, J. Huang, M. H. Saleh, D. Xing, S. Orsulic, M. S. Goldberg, Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model. Cancer Immunol. Res. 3, 1030-1041 (2015).
109. A. Gros, P. F. Robbins, X. Yao, Y. F. Li, S. Turcotte, E. Tran, J. R. Wunderlich, A. Mixon, S. Farid, M. E. Dudley, K.-i. Hanada, J. R. Almeida, S. Darko, D. C. Douek, J. C. Yang, S. A. Rosenberg, PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J. Clin. Invest. 124, 2246-2259 (2014).
110. J. D. Beane, G. Lee, Z. Zheng, M. Mendel, D. Abate-Daga, M. Bharathan, M. Black, N. Gandhi, Z. Yu, S. Chandran, M. Giedlin, D. Ando, J. Miller, D. Paschon, D. Guschin, E. J. Rebar, A. Reik, M. C. Holmes, P. D. Gregory, N. P. Restifo, S. A. Rosenberg, R. A. Morgan, S. A. Feldman, Clinical scale zinc finger nuclease-mediated gene editing of PD-1 in tumor infiltrating lymphocytes for the treatment of metastatic melanoma. Mol. Ther. 23, 1380-1390 (2015).
111. K. M. Mahoney, P. D. Rennert, G. J. Freeman, Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 14, 561-584 (2015).
112. G. L. Beatty, D. A. Torigian, E. G. Chiorean, B. Saboury, A. Brothers, A. Alavi, A. B. Troxel, W. Sun, U. R. Teitelbaum, R. H. Vonderheide, P. J. O'Dwyer, A phase I study of an agonist CD40 monoclonal antibody (CP-870, 893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin. Cancer Res. 19, 6286-6295 (2013).
113. J. C. Byrd, T. J. Kipps, I. W. Flinn, M. Cooper, O. Odenike, J. Bendiske, J. Rediske, S. Bilic, J. Dey, J. Baeck, S. O'Brien, Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia. Leuk. Lymphoma 53, 2136-2142 (2012).
114. P. Bansal-Pakala, A. G.-H. Jember, M. Croft, Signaling through OX40 (CD134) breaks peripheral T-cell tolerance. Nat. Med. 7, 907-912 (2001).
115. A. D. Weinberg, N. P. Morris, M. Kovacsovics-Bankowski, W. J. Urba, B. D. Curti, Science gone translational: The OX40 agonist story. Immunol. Rev. 244, 218-231 (2011).
116. I. Melero, W. W. Shuford, S. A. Newby, A. Aruffo, J. A. Ledbetter, K. E. Hellström, R. S. Mittler, L. Chen, Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat. Med. 3, 682-685 (1997).
117. C.-H. Chang, J. Qiu, D. O'Sullivan, M. D. Buck, T. Noguchi, J. D. Curtis, Q. Chen, M. Gindin, M. M. Gubin, G. J. W. Van der Windt, E. Tonc, R. D. Schreiber, E. J. Pearce, E. L. Pearce, Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229-1241 (2015).
118. P.-C. Ho, J. D. Bihuniak, A. N. Macintyre, M. Staron, X. Liu, R. Amezquita, Y.-C. Tsui, G. Cui, G. Micevic, J. C. Perales, S. H. Kleinstein, E. D. Abel, K. L. Insogna, S. Feske, J. W. Locasale, M. W. Bosenberg, J. C. Rathmell, S. M. Kaech, Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217-1228 (2015).
119. S. Wei, I. Kryczek, W. Zou, Regulatory T-cell compartmentalization and trafficking. Blood 108, 426-431 (2006).
120. W. Zou, Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295-307 (2006).
121. C. Ménétrier-Caux, T. Curiel, J. Faget, M. Manuel, C. Caux, W. Zou, Targeting regulatory T cells. Target Oncol. 7, 15-28 (2012).
122. T. R. Simpson, F. Li, W. Montalvo-Ortiz, M. A. Sepulveda, K. Bergerhoff, F. Arce, C. Roddie, J. Y. Henry, H. Yagita, J. D. Wolchok, K. S. Peggs, J. V. Ravetch, J. P. Allison, S. A. Quezada, Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695-1710 (2013).
123. F. S. Hodi, S. J. O'Day, D. F. McDermott, R. W. Weber, J. A. Sosman, J. B. Haanen, R. Gonzalez, C. Robert, D. Schadendorf, J. C. Hassel, W. Akerley, A. J. M. Van Den Eertwegh, J. Lutzky, P. Lorigan, J. M. Vaubel, G. P. Linette, D. Hogg, C. H. Ottensmeier, C. Lebbé, C. Peschel, I. Quirt, J. I. Clark, J. D. Wolchok, J. S. Weber, J. Tian, M. J. Yellin, G. M. Nichol, A. Hoos, W. J. Urba, Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711-723 (2010).
124. D. Schadendorf, F. S. Hodi, C. Robert, J. S. Weber, K. Margolin, O. Hamid, D. Patt, T.-T. Chen, D. M. Berman, J. D. Wolchok, 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, 1889-1894 (2015).
125. S. Wei, A. B. Shreiner, N. Takeshita, L. Chen, W. Zou, A. E. Chang, Tumor-induced immune suppression of in vivo effector T-cell priming is mediated by the B7-H1/PD-1 axis and transforming growth factor b. Cancer Res. 68, 5432-5438 (2008).
126. M. Ogura, T. Ishida, K. Hatake, M. Taniwaki, K. Ando, K. Tobinai, K. Fujimoto, K. Yamamoto, T. Miyamoto, N. Uike, M. Tanimoto, K. Tsukasaki, K. Ishizawa, J. Suzumiya, H. Inagaki, K. Tamura, S. Akinaga, M. Tomonaga, R. Ueda, Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J. Clin. Oncol. 32, 1157-1163 (2014).
127. B. Allard, S. Pommey, M. J. Smyth, J. Stagg, Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin. Cancer Res. 19, 5626-5635 (2013).
128. S. Wan, E. Zhao, I. Kryczek, L. Vatan, A. Sadovskaya, G. Ludema, D. M. Simeone, W. Zou, T. H. Welling, Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147, 1393-1404 (2014).
129. A. L. Mellor, D. H. Munn, IDO expression by dendritic cells: Tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762-774 (2004).
130. T. Maj, S. Wei, T. Welling, W. Zou, T cells and costimulation in cancer. Cancer J. 19, 473-482 (2013).
131. I. Kryczek, S. Wei, G. Zhu, L. Myers, P. Mottram, P. Cheng, L. Chen, G. Coukos, W. Zou, Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res. 67, 8900-8905 (2007).
132. T.-W. Sun, Q. Gao, S.-J. Qiu, J. Zhou, X.-Y. Wang, Y. Yi, J.-Y. Shi, Y.-F. Xu, Y.-H. Shi, K. Song, Y.-S. Xiao, J. Fan, B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence. Cancer Immunol. Immunother. 61, 2171-2182 (2012).
133. I. Yamato, M. Sho, T. Nomi, T. Akahori, K. Shimada, K. Hotta, H. Kanehiro, N. Konishi, H. Yagita, Y. Nakajima, Clinical importance of B7-H3 expression in human pancreatic cancer. Br. J. Cancer 101, 1709-1716 (2009).
134. L. Luo, A. I. Chapoval, D. B. Flies, G. Zhu, F. Hirano, S. Wang, J. S. Lau, H. Dong, K. Tamada, A. S. Flies, Y. Liu, L. Chen, B7-H3 enhances tumor immunity in vivo by costimulating rapid clonal expansion of antigen-specific CD8+ cytolytic T cells. J. Immunol. 173, 5445-5450 (2004).
135. R. Rahbar, A. Lin, M. Ghazarian, H.-L. Yau, S. Paramathas, P. A. Lang, A. Schildknecht, A. R. Elford, C. Garcia-Batres, B. Martin, H. K. Berman, W. L. Leong, D. R. McCready, M. Reedijk, S. J. Done, N. Miller, B. Youngson, W.-K. Suh, T. W. Mak, P. S. Ohashi, B7-H4 expression by nonhematopoietic cells in the tumor microenvironment promotes antitumor immunity. Cancer Immunol. Res. 3, 184-195 (2015).
136. L. Wang, R. Rubinstein, J. L. Lines, A. Wasiuk, C. Ahonen, Y. Guo, L.-F. Lu, D. Gondek, Y. Wang, R. A. Fava, A. Fiser, S. Almo, R. J. Noelle, VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J. Exp. Med. 208, 577-592 (2011).
137. D. B. Flies, X. Han, T. Higuchi, L. Zheng, J. Sun, J. J. Ye, L. Chen, Coinhibitory receptor PD-1H preferentially suppresses CD4+ T cell-mediated immunity. J. Clin. Invest. 124, 1966-1975 (2014).
138. D. B. Flies, T. Higuchi, L. Chen, Mechanistic assessment of PD-1H coinhibitory receptorinduced T cell tolerance to allogeneic antigens. J. Immunol. 194, 5294-5304 (2015).
139. K. Sakuishi, L. Apetoh, J. M. Sullivan, B. R. Blazar, V. K. Kuchroo, A. C. Anderson, Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187-2194 (2010).
140. H. Li, K. Wu, K. Tao, L. Chen, Q. Zheng, X. Lu, J. Liu, L. Shi, C. Liu, G. Wang, W. Zou, Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56, 1342-1351 (2012).
141. R. J. Johnston, L. Comps-Agrar, J. Hackney, X. Yu, M. Huseni, Y. Yang, S. Park, V. Javinal, H. Chiu, B. Irving, D. L. Eaton, J. L. Grogan, The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923-937 (2014).
142. J.-M. Chauvin, O. Pagliano, J. Fourcade, Z. Sun, H. Wang, C. Sander, J. M. Kirkwood, T.-h. T. Chen, M. Maurer, A. J. Korman, H. M. Zarour, TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J. Clin. Invest. 125, 2046-2058 (2015).
143. S.-R. Woo, M. E. Turnis, M. V. Goldberg, J. Bankoti, M. Selby, C. J. Nirschl, M. L. Bettini, D. M. Gravano, P. Vogel, C. L. Liu, S. Tangsombatvisit, J. F. Grosso, G. Netto, M. P. Smeltzer, A. Chaux, P. J. Utz, C. J. Workman, D. M. Pardoll, A. J. Korman, C. G. Drake, D. A. A. Vignali, Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917-927 (2012).
144. S. A. Rosenberg, J. C. Yang, N. P. Restifo, Cancer immunotherapy: Moving beyond current vaccines. Nat. Med. 10, 909-915 (2004).
145. S. Pilon-Thomas, A. Mackay, N. Vohra, J. J. Mulé, Blockade of programmed death ligand 1 enhances the therapeutic efficacy of combination immunotherapy against melanoma. J. Immunol. 184, 3442-3449 (2010).
146. J. Duraiswamy, G. J. Freeman, G. Coukos, Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res. 73, 6900-6912 (2013).
147. L. Karyampudi, P. Lamichhane, A.D. Scheid, K. R. Kalli, B. Shreeder, J.W. Krempski, M.D. Behrens, K. L. Knutson, Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody. Cancer Res. 74, 2974-2985 (2014).
148. S. A. Rosenberg, Decade in review-Cancer immunotherapy: Entering the mainstream of cancer treatment. Nat. Rev. Clin. Oncol. 11, 630-632 (2014).
149. R. H. I. Andtbacka, H. L. Kaufman, F. Collichio, T. Amatruda, N. Senzer, J. Chesney, K. A. Delman, L. E. Spitler, I. Puzanov, S. S. Agarwala, M. Milhem, L. Cranmer, B. Curti, K. Lewis, M. Ross, T. Guthrie, G. P. Linette, G. A. Daniels, K. Harrington, M. R. Middleton, W. H. Miller Jr., J. S. Zager, Y. Ye, B. Yao, A. Li, S. Doleman, A. VanderWalde, J. Gansert, R. S. Coffin, Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780-2788 (2015).
150. M. Nakanishi, D. W. Rosenberg, Multifaceted roles of PGE2 in inflammation and cancer. Semin. Immunopathol. 35, 123-137 (2013).
151. Y. Li, M. Fang, J. Zhang, J. Wang, Y. Song, J. Shi, W. Li, G. Wu, J. Ren, Z. Wang, W. Zou, L. Wang, Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity. Oncoimmunology 10.1080/2162402X.2015.1074374 (2015).
152. S. Zelenay, A. G. Van der Veen, J. P. Böttcher, K. J. Snelgrove, N. Rogers, S. E. Acton, P. Chakravarty, M. R. Girotti, R. Marais, S. A. Quezada, E. Sahai, C. Reis e Sousa, Cyclooxygenase-dependent tumor Growth through evasion of immunity. Cell 162, 1257-1270 (2015).
153. M. Cheng, Y. Chen, W. Xiao, R. Sun, Z. Tian, NK cell-based immunotherapy for malignant diseases. Cell. Mol. Immunol. 10, 230-252 (2013).
154. W. Zou, V. Machelon, A. Coulomb-Lhermin, J. Borvak, F. Nome, T. Isaeva, S. Wei, R. Krzysiek, I. Durand-Gasselin, A. Gordon, T. Pustilnik, D. T. Curiel, P. Galanaud, F. Capron, D. Emilie, T. J. Curiel, Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat. Med. 7, 1339-1346 (2001).
155. S. Wei, I. Kryczek, L. Zou, B. Daniel, P. Cheng, P. Mottram, T. Curiel, A. Lange, W. Zou, Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res. 65, 5020-5026 (2005).
156. A. Sistigu, T. Yamazaki, E. Vacchelli, K. Chaba, D. P. Enot, J. Adam, I. Vitale, A. Goubar, E. E. Baracco, C. Remédios, L. Fend, D. Hannani, L. Aymeric, Y. Ma, M. Niso-Santano, O. Kepp, J. L. Schultze, T. Tüting, F. Belardelli, L. Bracci, V. La Sorsa, G. Ziccheddu, P. Sestili, F. Urbani, M. Delorenzi, M. Lacroix-Triki, V. Quidville, R. Conforti, J.-P. Spano, L. Pusztai, V. Poirier-Colame, S. Delaloge, F. Penault-Llorca, S. Ladoire, L. Arnould, J. Cyrta, M.-C. Dessoliers, A. Eggermont, M. E. Bianchi, M. Pittet, C. Engblom, C. Pfirschke, X. Préville, G. Uzè, R. D. Schreiber, M. T. Chow, M. J. Smyth, E. Proietti, F. André, G. Kroemer, L. Zitvogel, Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat. Med. 20, 1301-1309 (2014).
157. S. Viaud, C. Flament, M. Zoubir, P. Pautier, A. LeCesne, V. Ribrag, J.-C. Soria, V. Marty, P. Vielh, C. Robert, N. Chaput, L. Zitvogel, Cyclophosphamide induces differentiation of Th17 cells in cancer patients. Cancer Res. 71, 661-665 (2011).
158. Y. Lee, S. L. Auh, Y. Wang, B. Burnette, Y. Wang, Y. Meng, M. Beckett, R. Sharma, R. Chin, T. Tu, R. R. Weichselbaum, Y.-X. Fu, Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: Changing strategies for cancer treatment. Blood 114, 589-595 (2009).
159. L. Deng, H. Liang, B. Burnette, M. Beckett, T. Darga, R. R. Weichselbaum, Y.-X. Fu, Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687-695 (2014).
160. S. Park, Z. Jiang, E. D. Mortenson, L. Deng, O. Radkevich-Brown, X. Yang, H. Sattar, Y. Wang, N. K. Brown, M. Greene, Y. Liu, J. Tang, S. Wang, Y.-X. Fu, The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 18, 160-170 (2010).
161. A. Beano, E. Signorino, A. Evangelista, D. Brusa, M. Mistrangelo, M. A. Polimeni, R. Spadi, M. Donadio, L. Ciuffreda, L. Matera, Correlation between NK function and response to trastuzumab in metastatic breast cancer patients. J. Transl. Med. 6, 25 (2008).
162. S. Wei, M. U. Egenti, S. Teitz-Tennenbaum, W. Zou, A. E. Chang, Effects of tumor irradiation on host T-regulatory cells and systemic immunity in the context of adoptive T-cell therapy in mice. J. Immunother. 36, 124-132 (2013).
163. C. Twyman-Saint Victor, A. J. Rech, A. Maity, R. Rengan, K. E. Pauken, E. Stelekati, J. L. Benci, B. Xu, H. Dada, P. M. Odorizzi, R. S. Herati, K. D. Mansfield, D. Patsch, R. K. Amaravadi, L. M. Schuchter, H. Ishwaran, R. Mick, D. A. Pryma, X. Xu, M. D. Feldman, T. C. Gangadhar, S. M. Hahn, E. J. Wherry, R. H. Vonderheide, A. J.Minn, Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373-377 (2015).
164. F. Klug, H. Prakash, P. E. Huber, T. Seibel, N. Bender, N. Halama, C. Pfirschke, R. H. Voss, C. Timke, L. Umansky, K. Klapproth, K. Schäkel, N. Garbi, D. Jäger, J. Weitz, H. Schmitz-Winnenthal, G. J. Hämmerling, P. Beckhove, Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24, 589-602 (2013).
165. S. J. Dovedi, A. L. Adlard, G. Lipowska-Bhalla, C. McKenna, S. Jones, E. J. Cheadle, I. J. Stratford, E. Poon, M. Morrow, R. Stewart, H. Jones, R. W. Wilkinson, J. Honeychurch, T. M. Illidge, Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 74, 5458-5468 (2014).
166. A. B. Sharabi, C. J. Nirschl, C. M. Kochel, T. R. Nirschl, B. J. Francica, E. Velarde, T. L. Deweese, C. G. Drake, Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol. Res. 3, 345-355 (2015).
167. L. Zitvogel, O. Kepp, G. Kroemer, Decoding cell death signals in inflammation and immunity. Cell 140, 798-804 (2010).
168. S. Shalapour, J. Font-Burgada, G. Di Caro, Z. Zhong, E. Sanchez-Lopez, D. Dhar, G. Willimsky, M. Ammirante, A. Strasner, D. E. Hansel, C. Jamieson, C. J. Kane, T. Klatte, P. Birner, L. Kenner, M. Karin, Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521, 94-98 (2015).
169. J. Ozao-Choy, G. Ma, J. Kao, G. X. Wang, M. Meseck, M. Sung, M. Schwartz, C. M. Divino, P.-Y. Pan, S.-H. Chen, The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res. 69, 2514-2522 (2009).
170. C. J. Scotton, J. L. Wilson, D. Milliken, G. Stamp, F. R. Balkwill, Epithelial cancer cell migration: A role for chemokine receptors? Cancer Res. 61, 4961-4965 (2001).
171. I. Kryczek, A. Lange, P. Mottram, X. Alvarez, P. Cheng, M. Hogan, L. Moons, S. Wei, L. Zou, V. Machelon, D. Emilie, M. Terrassa, A. Lackner, T. J. Curiel, P. Carmeliet, W. Zou, CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res. 65, 465-472 (2005).
172. C. Feig, J. O. Jones, M. Kraman, R. J. B. Wells, A. Deonarine, D. S. Chan, C. M. Connell, E. W. Roberts, Q. Zhao, O. L. Caballero, S. A. Teichmann, T. Janowitz, D. I. Jodrell, D. A. Tuveson, D. T. Fearon, Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl. Acad. Sci. U.S.A. 110, 20212-20217 (2013).
173. T. K. Choueiri, D. J. Figueroa, A. P. Fay, S. Signoretti, Y. Liu, R. Gagnon, K. Deen, C. Carpenter, P. Benson, T. H. Ho, L. Pandite, P. De Souza, T. Powles, R. J. Motzer, Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: Results from COMPARZ, a randomized controlled trial. Clin. Cancer Res. 21, 1071-1077 (2015).
174. I. Kryczek, K. Wu, E. Zhao, S. Wei, L. Vatan, W. Szeliga, E. Huang, J. Greenson, A. Chang, J. Rolinski, P. Radwan, J. Fang, G. Wang, W. Zou, IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J. Immunol. 186, 4388-4395 (2011).
175. P. Sansone, G. Storci, S. Tavolari, T. Guarnieri, C. Giovannini, M. Taffurelli, C. Ceccarelli, D. Santini, P. Paterini, K. B. Marcu, P. Chieco, M. Bonafè, IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J. Clin. Invest. 117, 3988-4002 (2007).
176. L. L. C.Marotta, V. Almendro, A.Marusyk, M. Shipitsin, J. Schemme, S. R.Walker, N. Bloushtain-Qimron, J. J. Kim, S. A. Choudhury, R. Maruyama, Z. Wu, M. Gönen, L. A. Mulvey, M. O. Bessarabova, S. J. Huh, S. J. Silver, S. Y. Kim, S. Y. Park, H. E. Lee, K. S. Anderson, A. L. Richardson, T. Nikolskaya, Y. Nikolsky, X. S. Liu, D. E. Root, W. C. Hahn, D. A. Frank, K. Polyak, The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24-stem cell-like breast cancer cells in human tumors. J. Clin. Invest. 121, 2723-2735 (2011).
177. C. Ginestier, S. Liu, M. E. Diebel, H. Korkaya, M. Luo, M. Brown, J. Wicinski, O. Cabaud, E. Charafe-Jauffret, D. Birnbaum, J.-L. Guan, G. Dontu, M. S. Wicha, CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J. Clin. Invest. 120, 485-497 (2010).