Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies

Abstract

Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores preexisting T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/ PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.

Keywords

PD-1/PD-L1 interaction / checkpoint blockade / molecular basis / therapeutic antibody

References

[1] Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 8:765–772

[2] Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA (2009) Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114:1537–1544

[3] Bang YJ, Chung HC, Shankaran V, Geva R, Catenacci DVT, Gupta S, Eder JP, Berger R, Gonzalez EJ, Ray A, Dolled-Filhart M, Emancipator K, Pathiraja K, Lunceford JK, Cheng JD, Koshiji J, Muro K (2015) Relationship between PD-L1 expression and clinical outcomes in patients with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in KEYNOTE-012. J Clin Oncol 33

[4] Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006a) “Exhausted” T cells: good or bad depends on your point of view- Restoring function in exhausted CD8 T cells during chronic viral infection. Liver Transpl 12:1167–1168

[5] Barber DL, Wherry EJ, Masopust D, Zhu BG, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006b) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687

[6] Benvenuti F, Lagaudriere-Gesbert C, Grandjean I, Jancic C, Hivroz C, Trautmann A, Lantz O, Amigorena S (2004) Dendritic cell maturation controls adhesion, synapse formation, and the duration of the interactions with naive T lymphocytes. J Immunol 172:292–301

[7] Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DAA, Wherry EJ (2009) Coregulation of CD8(+) Tcell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10:29–37

[8] Blank C, Kuball J, Voelkl S, Wiendl H, Becker B, Walter B, Majdic O, Gajewski TF, Theobald M, Andreesen R (2006) Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro. Int J Cancer 119:317–327

[9] Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL (2010) 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

[10] Bretscher P, Cohn M (1970) A theory of self-nonself discrimination. Science 169:1042–1049

[11] Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, Greenfield EA, Freeman GJ (2003) Blockade of programmed death-1 Ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 170:1257–1266

[12] Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ (2007) Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27:111–122

[13] Callahan MK, Postow MA, Wolchok JD (2016) Targeting T Cell coreceptors for cancer therapy. Immunity 44:1069–1078

[14] Chang WS, Kim JY, Kim YJ, Kim YS, Lee JM, Azuma M, Yagita H, Kang CY (2008) Cutting edge: programmed death-1/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy. J Immunol 181:6707–6710

[15] Chapman PB, D’Angelo SP, Wolchok JD (2015) Rapid eradication of a bulky melanoma mass with one dose of immunotherapy. N Eng J Med 372:2073–2074

[16] Chatterjee P, Patsoukis N, Freeman GJ, Boussiotis VA (2013) Distinct roles of PD-1 Itsm and ITIM In regulating interactions with SHP-2, ZAP-70 and Lck, and PD-1-mediated inhibitory function. Blood 122:191

[17] Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL(2004) SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 173:945–954

[18] Chemnitz JM, Eggle D, Driesen J, Classen S, Riley JL, Debey-Pascher S, Beyer M, Popov A, Zander T, Schultze JL (2007) RNA fingerprints provide direct evidence for the inhibitory role of TGF beta and PD-1 on CD4(+) T cells in Hodgkin lymphoma. Blood 110:3226–3233

[19] Chen L, Han X (2015) Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest 125:3384–3391

[20] Chen Y, Liu P, Gao F, Cheng H, Qi J, Gao GF (2010) A dimeric structure of PD-L1: functional units or evolutionary relics? Protein Cell 1:153–160

[21] Cheng X, Veverka V, Radhakrishnan A, Waters LC, Muskett FW, Morgan SH, Huo J, Yu C, Evans EJ, Leslie AJ (2013) Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem 288:11771–11785

[22] Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, Stuart DI, van der Merwe PA, Davis SJ (2002) The interaction properties of costimulatory molecules revisited. Immunity 17:201–210

[23] Cunningham AJ, Lafferty KJ (1977) A simple conservative explanation of the H-2 restriction of interactions between lymphocytes. Scand J Immunol 6:1–6

[24] Curiel TJ, Wei S, Dong HD, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9:562–567

[25] Dong HD, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu GF, Tamada K(2002) Tumorassociated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793

[26] Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH (2009) PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206:3015–3029

[27] Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC (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

[28] Gandini S, Massi D, Mandala M (2016) PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis. Crit Rev Oncol Hematol 100:88–98

[29] Gao GF, Jakobsen BK (2000) Molecular interactions of coreceptor CD8 and MHC class I: the molecular basis for functional coordination with the T-cell receptor. Immunol Today 21:630–636

[30] Gao GF, Rao Z, Bell JI (2002) Molecular coordination of alphabeta T-cell receptors and coreceptors CD8 and CD4 in their recognition of peptide-MHC ligands. Trends Immunol 23:408–413

[31] Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018–2028

[32] Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G, Elkum N, Alshabanah M, Bin Amer S, Tulbah A (2006) 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

[33] Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8(+) T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 104:3360–3365

[34] Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515:563–567

[35] Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y (2010) Tumor cell expression of programmed Cell Death-1 Ligand 1 Is a prognostic factor for malignant melanoma. Cancer 116:1757–1766

[36] Hirano F, Kaneko K, Tamura H, Dong HD, Wang SD, Ichikawa M, Rietz C, Flies DB, Lau JS, Zhu GF (2005) Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65:1089–1096

[37] Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of Pd-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell-death. EMBO J 11:3887–3895

[38] Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 99:12293–12297

[39] John LB, Devaud C, Duong CPM, Yong CS, Beavis PA, Haynes NM, Chow MT, Smyth MJ, Kershaw MH, Darcy PK (2013) Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res 19:5636–5646

[40] Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, Maeda T, Nagata Y, Kitanaka A, Mizuno S (2016) Aberrant PD-L1 expression through 3 ‘-UTR disruption in multiple cancers. Nature 534:402

[41] Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O’Shea MA, Fauci AS (2008) The common gamma-Chain Cytokines IL-2, IL- 7, IL-15, and IL-21 induce the expression of programmed Death-1 and its ligands. J Immunol 181:6738–6746

[42] Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, Elco CP, Lee N, Juneja VR, Zhan Q (2015) Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162:1242–1256

[43] Lafferty KJ, Cunningham AJ (1975) A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci 53:27–42

[44] Latchman Y, Wood C, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001a) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268

[45] Latchman Y, Wood C, Chemova T, Iwai Y, Malenkovich N, Long A, Bourque K, Boussiotis V, Nishimura H, Honjo T (2001b) PDL2, a novel B7 homologue, is a second ligand for PD-1 and inhibits T cell activation. Faseb J 15:A345–A345

[46] Lazar-Molnar E, Yan Q, Cao E, Ramagopal U, Nathenson SG, Almo SC (2008) Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. Proc Natl Acad Sci U S A 105:10483–10488

[47] Lesterhuis WJ, Steer H, Lake RA (2011) PD-L2 is predominantly expressed by Th2 cells. Mol Immunol 49:1–3

[48] Li Y, Li F, Jiang F, Lv X, Zhang R, Lu A, Zhang G (2016) A minireview for cancer immunotherapy: molecular understanding of PD-1/PD-L1 pathway & translational blockade of immune checkpoints. Int J Mol Sci 17:1151

[49] Lin DY, Tanaka Y, Iwasaki M, Gittis AG, Su HP, Mikami B, Okazaki T, Honjo T, Minato N, Garboczi DN (2008) The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc Natl Acad Sci U S A 105:3011–3016

[50] Liu JZ, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, Saudemont A, Quesnel B (2007) Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-gamma and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 110:296–304

[51] Liu Y, Yu YY, Yang SG, Zeng B, Zhang ZH, Jiao GH, Zhang Y, Cai LM, Yang RC (2009) Regulation of arginase I activity and expression by both PD-1 and CTLA-4 on the myeloid-derived suppressor cells. Cancer Immunol Immunother 58:687–697

[52] Liu K, Tan S, Chai Y, Chen D, Song H, Zhang CW, Shi Y, Liu J, Tan W, Lyu J, Gao S, Yan J, Qi J, Gao GF (2016) Structural basis of anti-PD-L1 monoclonal antibody avelumab for tumor therapy. Cell Res.

[53] Mahoney KM, Rennert PD, Freeman GJ (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Disc 14:561–584

[54] Maute RL, Gordon SR, Mayer AT, McCracken MN, Natarajan A, Ring NG, Kimura R, Tsai JM, Manglik A, Kruse AC (2015) Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging. Proc Natl Acad Sci U S A 112: E6506–E6514

[55] Na Z, Yeo SP, Bharath SR, Bowler MW, Balikci E, Wang CI, Song H (2016) Structural basis for blocking PD-1-mediated immune suppression by therapeutic antibody pembrolizumab. Cell Res.

[56] Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, Minato N, Yagita H, Nakano T, Honjo T (1996) Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4(-)CD8(-)) thymocytes. Int Immunol 8:773–780

[57] Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD- 1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151

[58] Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M (2007) Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 13:2151–2157

[59] O’Donnell PH, Pilmack ER, Bellmunt J, Berger R, Montgomery RB, Heath K, Dolled-Filhart M, Pathiraja K, Gause CK, Cheng JD, Perini RF, Gupta S (2015). Pembrolizumab (Pembro; MK-3475) for advanced urothelial cancer: Results of a phase IB study. J Clin Oncol 33.

[60] Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K (2005) Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 11:2947–2953

[61] Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T (2001) PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 98:13866–13871

[62] Palucka AK, Coussens LM (2016) The basis of oncoimmunology. Cell 164:1233–1247

[63] Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, Precopio ML, Schacker T, Roederer M, Douek DC (2006) PD-1 is a regulator of virus-specific CD8(+) T cell survival in HIV infection. J Exp Med 203:2281–2292

[64] Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372:2006–2017

[65] Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, Bellmunt J, Burris HA, Petrylak DP, Teng SL (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558–562

[66] Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128

[67] Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E (2015a) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330

[68] Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M (2015b) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521–2532

[69] Schildberg FA, Klein SR, Freeman GJ, Sharpe AH (2016) Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity 44:955–972

[70] Schwartz JC, Zhang X, Fedorov AA, Nathenson SG, Almo SC (2001) Structural basis for co-stimulation by the human CTLA-4/ B7-2 complex. Nature 410:604–608

[71] Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu YC, Jussif JM, Carter LL, Wood CR (2004) PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3 zeta signalosome and downstream signaling to PKC theta. Febs Lett 574:37–41

[72] Shimauchi T, Kabashima K, Nakashima D, Sugita K, Yamada Y, Hino R, Tokura Y (2007) Augmented expression of programmed death-1 in both neoplastic and non-neoplastic CD4(+) T-cells in adult T-cell leukemia/lymphoma. Int J Cancer 121:2585–2590

[73] Tan S, Gao GF (2015) New hope for cancer treatment: Cancer Immunotherapy. Chin Sci Bull 60:3155–3157 (in Chinese)

[74] Tanguy Y. Seiwert, B.B., Jared Weiss, Joseph Paul Eder, Jennifer Yearley, Erin Murphy, Michael Nebozhyn, Terri McClanahan, Mark Ayers, Jared K. Lunceford, Ranee Mehra, Karl Heath, Jonathan D. Cheng and Laura Q. Chow(2015). Inflamedphenotype gene expression signatures to predict benefit from the anti-PD-1 antibody pembrolizumab in PD-L1+ head and neck cancer patients. J Clin Oncol 33.

[75] Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong HD, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen LP (2005) Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. J Urol 173:169

[76] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454

[77] Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32:1020–1030

[78] Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H (2001) B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 193:839–845

[79] Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJM, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571

[80] Wang HY, Lee DA, Peng G, Guo Z, Li Y, Kiniwa Y, Shevach EM, Wang RF (2004) Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 20:107–118

[81] Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 77:4911–4927

[82] Wu CP, Zhu YB, Jiang JT, Zhao JM, Zhang XG, Xu N (2006) Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 108:19–24

[83] Xiao Y, Yu S, Zhu B, Bedoret D, Bu X, Francisco LM, Hua P, Duke-Cohan JS, Umetsu DT, Sharpe AH (2014) RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med 211:943–959

[84] Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K(2002) Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 169:5538–5545

[85] Zak KM, Kitel R, Przetocka S, Golik P, Guzik K, Musielak B, Domling A, Dubin G, Holak TA (2015) Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1. Structure 23:2341–2348

[86] Zak KM, Grudnik P, Guzik K, Zieba BJ, Musielak B, Domling A, Dubin G, Holak TA (2016) Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget 7:30323–30335

[87] Zhan MM, Hu XQ, Liu XX, Ruan BF, Xu J, Liao C (2016) From monoclonal antibodies to small molecules: the development of inhibitors targeting the PD-1/PD-L1 pathway. Drug Discov Today 21:1027–1036

[88] Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, Cammer M, Chen L, Zhang ZY, Edidin MA (2004) Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 20:337–347

[89] Zhang B, Chikuma S, Hori S, Fagarasan S, Honjo T (2016) Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model. Proc Natl Acad Sci U S A 113:8490–8495

[90] Zou W, Wolchok JD, Chen L (2016) PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med 8:328rv324

RIGHTS & PERMISSIONS

The Author(s) 2016. This article is published with open access at Springerlink.com and journal.hep.com.cn