PD-1/PD-Ls signaling pathway and the application of anti-PD-1/PD-Ls antibodies in cancer therapy

PAN Jiajia; JIA Xiaoqing; HUANG Gang; ZHANG Yubin

doi:10.11665/j.issn.1000-5048.20160102

Journal of China Pharmaceutical University > 2016 > 47(1): 9-18. > DOI: 10.11665/j.issn.1000-5048.20160102

PAN Jiajia, JIA Xiaoqing, HUANG Gang, ZHANG Yubin. PD-1/PD-Ls signaling pathway and the application of anti-PD-1/PD-Ls antibodies in cancer therapy[J]. Journal of China Pharmaceutical University, 2016, 47(1): 9-18. DOI: 10.11665/j.issn.1000-5048.20160102

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PD-1/PD-Ls signaling pathway and the application of anti-PD-1/PD-Ls antibodies in cancer therapy

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Abstract

Programmed death-1(PD-1)is a major co-suppression receptor expressed on T cells. Binding with its ligands(PD-L1 and PD-L2), PD-1 can inhibit T cell proliferation, activation and cytokine secretion. In normal organs, PD-1/PD-Ls signaling pathway plays an important role in maintaining immune tolerance, while suppressing T cell immune response and promoting tumor immune escape during tumorigenesis. This article reviews the research progress on PD-1/PD-Ls signaling pathway from the structure and expression of PD-1/PD-Ls, the mechanism of the signaling pathway as well as the expression characteristics of soluble form of PD-1/PD-L1(sPD-1/sPD-L1), and summarizes the categories of anti-PD-1/ PD-Ls antibodies and their clinical trials in cancer immunotherapy.
- programmed death-1,
- programmed death-1 ligands,
- monoclonal antibody,
- antitumor,
- progress

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[1]	Hamid O,Carvajal RD.Anti-programmed death-1 and anti-programmed death-ligand 1 antibodies in cancer therapy[J].Expert Opin Biol Ther,2013,13(6):847-861.
[2]	Saudemont A,Quesnel B.In a model of tumor dormancy,long-term persistent leukemic cells have increased B7-H1 and B7.1 expression and resist CTL-mediated lysis[J].Blood,2004,104(7):2124-2133.
[3]	Zhang L,Gajewski TF,Kline J.PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model[J].Blood,2009,114(8):1545-1552.
[4]	Dai S,Jia R,Zhang X,et al.The PD-1/PD-Ls pathway and autoimmune diseases[J].Cell Immunol,2014,290(1):72-79.
[5]	López-Medina M,Carrillo-Martín I,Leyva-Rangel J,et al.Salmonella impairs CD8 T cell response through PD-1:PD-L axis[J].Immunobiology,2015,220(12):1369-1380.
[6]	La X,Zhang F,Li Y,et al.Upregulation of PD-1 on CD4⁺CD25⁺T cells is associated with immunosuppression in liver of mice infected with Echinococcus multilocularis[J].Int Immunopharmacol,2015,26(2):357-366.
[7]	Li T,Ma R,Zhu JY,et al.PD-1/PD-L1 costimulatory pathway-induced mouse islet transplantation immune tolerance[J].Transplant Proc,2015,47(1):165-170.
[8]	Ohaegbulam KC,Assal A,Lazar-Molnar E,et al.Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway[J].Trends Mol Med,2015,21(1):24-33.
[9]	Swaika A,Hammond WA,Joseph RW.Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy[J].Mol Immunol,2015,6(7):4-17.
[10]	Sunshine J,Taube JM.PD-1/PD-L1 inhibitors[J].Curr Opin Pharmacol,2015,23: 32-38.
[11]	Chemnitz JM, Parry RV, Nichols KE, et al. 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].J Immunol,2004,173(2):945-954.
[12]	Thompson RH,Dong H,Lohse CM,et al.PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma[J].Clin Cancer Res,2007,13(6):1757-1761.
[13]	Zhang Y,Huang S,Gong D,et al.Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8⁺;T lymphocytes in human non-small cell lung cancer[J].Cell Mol Immunol,2010,7(5):389-395.
[14]	Kleffel S,Posch C,Barthel SR,et al.Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth[J].Cell,2015,162(6):1242-1256.
[15]	Messal N,Serriari NE,Pastor S,et al.PD-L2 is expressed on activated human T cells and regulates their function[J].Mol Immunol,2011,48(15):2214-2219.
[16]	Lesterhuis WJ, Steer H, Lake RA. PD-L2 is predominantly expressed by Th2 cells[J].Mol Immunol,2011,49(1):1-3.
[17]	Ghiotto M,Gauthier L,Serriari N,et al.PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1[J].Int Immunol,2010,22(8):651-660.
[18]	Chapoval AI,Ni J,Lau JS,et al.B7-H3:a costimulatory molecule for T cell activation and IFN-gamma production[J].Nat Immunol,2001,2(3):269-274.
[19]	Chikuma S,Terawaki S,Hayashi T,et al.PD-1-mediated suppression of IL-2 production induces CD8⁺T cell anergy in vivo[J].J Immunol,2009,182(11):6682-6689.
[20]	Bishop KD,Harris JE,Mordes JP,et al.Depletion of the programmed death-1 receptor completely reverses established clonal anergy in CD4(+)T lymphocytes via an interleukin-2-dependent mechanism[J].Cell Immunol,2009,256(1/2):86-91.
[21]	Wang S,Bajorath J,Flies DB,et al.Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD-1 interaction[J].J Exp Med,2003,197(9):1083-1091.
[22]	Elhag O A,Hu XJ,Wen-Ying Z,et al.Reconstructed adeno-associated virus with the extracellular domain of murine PD-1 induces antitumor immunity[J].Asian Pac J Cancer Prev,2012,13(8):4031-4036.
[23]	Song MY, Park SH, Nam HJ, et al. Enhancement of vaccine-induced primary and memory CD8(+)T-cell responses by soluble PD-1[J].J Immunother,2011,34(3):297-306.
[24]	Kuipers H,Muskens F,Willart M,et al.Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4⁺T cell activation[J].Eur J Immunol,2006,36(9):2472-2482.
[25]	Wan B,Nie H,Liu A,et al.Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis[J].J Immunol,2006,177(12):8844-8850.
[26]	Frigola X,Inman B A,Krco CJ,et al.Soluble B7-H1:differences in production between dendritic cells and T cells[J].Immunol Lett,2012,142(1):78-82.
[27]	Frigola X,Inman BA,Lohse CM,et al.Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma[J].Clin Cancer Res,2011,17(7):1915-1923.
[28]	Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer[J].N Engl J Med,2012,366(26):2443-2454.
[29]	Topalian SL,Sznol M,McDermott DF,et al.Survival,durable tumor remission,and long-term safety in patients with advanced melanoma receiving nivolumab[J].J Clin Oncol,2014,32(10):1020-1030.
[30]	Robert C,Long GV,Brady B,et al.Nivolumab in previously untreated melanoma without BRAF mutation[J].N Engl J Med,2015,372(4):320-330.
[31]	Weber JS,D′Angelo SP,Minor D,et al.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[J].Lancet Oncol,2015,16(4):375-384.
[32]	Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer[J].N Engl J Med,2015,373(2):123-135.
[33]	Motzer RJ,Rini BI,McDermott D F,et al.Nivolumab for metastatic renal cell carcinoma:results of a randomized phase II trial[J].J Clin Oncol,2015,33(13):1430-1437.
[34]	Ansell SM,Lesokhin AM,Borrello I,et al.PD-1 blockade with nivolumab in relapsed or refractory Hodgkin′s lymphoma[J].N Engl J Med,2015,372(4):311-319.
[35]	Hamid O,Robert C,Daud A,et al.Safety and tumor responses with lambrolizumab(anti-PD-1)in melanoma[J].N Engl J Med,2013,369(2):134-144.
[36]	Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma[J].N Engl J Med,2015,372(26):2521-2532.
[37]	Moskowitz CH,Ribrag V,Michot JM,et al.PD-1 blockade with the monoclonal antibody pembrolizumab(MK-3475)in patients with classical Hodgkin lymphoma after brentuximab vedotin failure:preliminary results from a phase 1b study(KEYNOTE-013)[J].Blood,2014,124(21):290.
[38]	Seiwert TY,Burtness B,Weiss J,et al.A phase Ib study of MK-3475 in patients with human papillomavirus(HPV)-associated and non-HPV-associated head and neck(H/N)cancer[C]//ASCO Annual Meeting Proceedings,2014,32(15 Suppl):6011.
[39]	Atkins MB,Kudchadkar RR,Sznol M,et al.Phase 2,multicenter,safety and efficacy study of pidilizumab in patients with metastatic melanoma[C]//ASCO Annual Meeting Proceedings,2014,32(15 Suppl):9001.
[40]	Westin JR,Chu F,Zhang M,et al.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[J].Lancet Oncol,2014,15(1):69-77.
[41]	Mkrtichyan M,Najjar YG,Raulfs EC,et al.B7-DC-Ig enhances vaccine effect by a novel mechanism dependent on PD-1 expression level on T cell subsets[J].J Immunol,2012,189(5):2338-2347.
[42]	Powles T,Eder JP,Fine GD,et al.MPDL3280A(anti-PD-L1)treatment leads to clinical activity in metastatic bladder cancer[J].Nature,2014,515(7528):558-562.
[43]	Herbst RS,Gordon MS,Fine GD,et al.A study of MPDL3280A,an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors[C]//ASCO Annual Meeting Proceedings,2013,31(15 Suppl):3000.
[44]	Emens LA,Braiteh FS,Cassier P,et al.Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer(TNBC)[J].Cancer Res,2015,75(15 Suppl):2859-2859.
[45]	Ibrahim R,Stewart R,Shalabi A.PD-L1 blockade for cancer treatment:MEDI4736[J].Semin Oncol,2015,42(3):474-483.
[46]	Segal NH,Antonia SJ,Brahmer JR,et al.Preliminary data from a multi-arm expansion study of MEDI4736,an anti-PD-L1 antibody[J].J Clin Oncol,2014,32(15 suppl):134136-134144.
[47]	Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer[J].N Engl J Med,2012,366(26):2455-2465.
[48]	Disis ML,Patel MR,Pant S,et al.Avelumab(MSB0010718C),an anti-PD-L1 antibody,in patients with previously treated,recurrent or refractory ovarian cancer:a phase Ib,open-label expansion trial[C]//ASCO Annual Meeting Proceedings,2015,33(15 Suppl):5509.
[49]	McDermott DF,Atkins MB.PD-1 as a potential target in cancer therapy[J].Cancer Med,2013,2(5):662-673.
[50]	Teixido C,Karachaliou N,Gonzalez-Cao M,et al.Assays for predicting and monitoring responses to lung cancer immunotherapy[J].Cancer Biol Med,2015,12(2):87-95.

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PD-1/PD-Ls signaling pathway and the application of anti-PD-1/PD-Ls antibodies in cancer therapy

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