PD-1和PD-L1在肿瘤免疫逃逸中的作用机制及临床意义
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摘要
随着人们对肿瘤免疫微环境的深入研究,发现肿瘤细胞的免疫逃逸是造成肿瘤进展的关键原因,其分子机制也成为肿瘤免疫治疗研究的重点问题之一。近年研究表明程序性死亡受体-1(programmed death receptor-1,PD-1)与程序性死亡配体-1(programmed death ligand-1,PD-L1)与肿瘤发生、发展有密切联系。其中,PD-1是T细胞介导免疫反应中的重要抑制性免疫检查点,肿瘤细胞通过表达PD-L1,与肿瘤浸润淋巴细胞的PD-1结合,诱导淋巴细胞的凋亡,从而抵抗淋巴细胞的杀伤作用,最终造成肿瘤发生免疫逃逸。本文对PD-1和PD-L1在肿瘤免疫逃逸中的作用机制及在肿瘤治疗中的临床意义作一综述。
With the further study of tumor immune microenvironment,it is found that immune escape of tumor cells is the key cause of tumor progression,and its molecular mechanisms have become the one of focused question regarding tumor immunotherapy research.Recent studies demonstrated that programmed death receptor-1(PD-1) and programmed death ligand-1(PD-L1) has closely correlation with occurrence and progression of tumor.Thereinto,PD-1 is an important check-point for the inhibit immunity in the immune response induced by T cells.The expression of PD-L1 by tumor cells is integrated with PD-1 of lymphocytes infiltrated by tumor,lead to the apoptosis of lymphocytes,so as to resist the lethal effect of lymphocytes,which cause the cancer immune escape finally.This review concludes the mechanisms of PD-1 and PD-L1 in cancer immune escape and clinical significance of PD-1 and PD-L1 in the tumor treatment.
With the further study of tumor immune microenvironment,it is found that immune escape of tumor cells is the key cause of tumor progression,and its molecular mechanisms have become the one of focused question regarding tumor immunotherapy research.Recent studies demonstrated that programmed death receptor-1(PD-1) and programmed death ligand-1(PD-L1) has closely correlation with occurrence and progression of tumor.Thereinto,PD-1 is an important check-point for the inhibit immunity in the immune response induced by T cells.The expression of PD-L1 by tumor cells is integrated with PD-1 of lymphocytes infiltrated by tumor,lead to the apoptosis of lymphocytes,so as to resist the lethal effect of lymphocytes,which cause the cancer immune escape finally.This review concludes the mechanisms of PD-1 and PD-L1 in cancer immune escape and clinical significance of PD-1 and PD-L1 in the tumor treatment.
引文
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[23] Deng C,Li Z,Guo S,et al.Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma[J].Oncoimmunology,2016,6(2):e1269047.
[24] Nomi T,Sho M,Akahori T,et al.Clinical significance and therapeutic potential of the programmed death/1 ligand/programmed death-1 pathway in human pancreatic cancer[J].Clin Cancer Res,2007,13(7):2151-2157.
[25] Hitzler M,Majdic O,Heine G,et al.Human Langerhans cells control Th cells via programmed death-ligand 1 in response to bacterial stimuli and nickel-induced contact allergy[J].PLoS One,2012,7(10):e46776.
[26] Zhong AY.Regulatory role of the PD-1/PD-L1 signaling pathway in Treg cells in lung cancer[D].Suzhou:Suzhou university,2016.
[27] Jiang L,Tang C,Gong Y,et al.PD-1/PD-L1 regulates Treg differentiation in pregnancy-induced hypertension[J].Braz J Med Biol Res,2018,51(8):e7334.
[28] Francisco LM,Salinas VH,Brown KE,et al.PD-L1 regulates the development,maintenance,and function of induced regulatory T cells[J].J Exp Med,2009,206(13):3015-3029.
[29] Zhao L,Li C,Liu F,et al.A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/Akt/mTOR signaling pathway[J].Onco Targets Ther,2017,10:2115-2126.
[30] Park HJ,Park JS,Jeong YH,et al.PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells[J].J Immunol,2015,194(12):5801-5811.
[31] Chiu YM,Tsai CL,Kao JT,et al.PD-1 and PD-L1 up-regulation promotes T-cell apoptosis in gastric adenocarcinoma[J].Anticancer Res,2018,38(4):2069-2078.
[32] Shi F,Shi M,Zeng Z,et al.PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients[J].Int J Cancer,2011,128(4):887-896.
[33] Dong H,Strome SE,Salomao DR,et al.Tumor-associated B7H1 promotes T-cell apoptosis:A potential mahcanism of immune evasion[J].Nat Med,2002,8(8):4661-4665.
[34] Watanabe T,Bertoletti A,Tanoto TA.PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection[J].J Viral Hepat,2010,17(7):453-458.
[35] Duraiswamy J,Freeman GJ,Coukos G.Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer[J].Cancer Res,2013,73(23):69000-69012.
[36] Chen D,Tang P,Liu L,et al.Bone marrow-derived mesenchymal stem cells promote cell proliferation of multiple myeloma through inhibiting T cell immune responses via PD-1/PD-L1 pathway[J].Cell Cycle,2018,2018:1-10.
[37] Que Y,Xiao W,Guan YX,et al.PD-L1 Expression is associated with FOXP3+ regulatory T-cell infiltration of soft tissue sarcoma and poor patient prognosis[J].J Cancer,2017,8(11):2018-2025.
[38] Tai H,Yang Q,Wu Z,et al.PD-L1 expression predicts a distinct prognosis in Krukenberg tumor with corresponding origins[J].J Immunol Res,2018,2018:9485285.
[39] Salhab M,Migdady Y,Donahue M,et al.Immunohistochemical expression and prognostic value of PD-L1 in Extrapulmonary small cell carcinoma:A single institution experience[J].J Immunother Cancer,2018,6(1):42.
[40] Sheng Z,Zhu X,Sun Y,et al.The efficacy of anti-PD-1/PD-L1 therapy and its comparison with EGFR-TKIs for advanced non-small cell lung cancer[J].Oncotarget,2017,8(34):57826-57835.
[41] Konishi J,Yamazaki K,Azuma M,et al.B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression[J].Clin Cancer Res,2004,10(15):5094-5100.
[42] Mkrtichyan M,Najjar YG,Raulfs EC,et al.Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms[J].Eur J Immunol,2011,41(10):2977-2986.
[2] Eckert AW,Wickenhauser C,Salins PC,et al.Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma[J].J Transl Med,2016,14:85.
[3] Ma W,Gilligan BM,Yuan J,et al.Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy[J].J Hematol Oncol,2016,9(1):47.
[4] Kim JM,Chen DS.Immune escape to PD-L1/PD-1 blockade:Eeven steps to success(or failure)[J].Ann Oncol,2016,27(8):1492-504.
[5] Du GQ,Wang J.PD-L1/PD-1 pathway and tumors[J].Progress of Anatomical Sciences,2017,23(5):525-528.[杜国强,王瑾.PD-1/PD-L1信号通路与肿瘤[J].解剖科学进展,2017,23(5):525-528.]
[6] Kitano A,Ono M,Yoshida M,et al.Tumour-infiltrating lymphocytes are correlated with higher expression levels of PD-1 and PD-L1 in early breast cancer[J].ESMO Open,2017,2(2):e000150.
[7] Zak KM,Kitel R,Przetocka S,et al.Structure of the complex of human programmed death 1,PD-1,and its ligand PD-L1[J].Structure,2015,23(12):2341-2348.
[8] Zhang X,Schwartz JC,Guo X,et al.Structural and functional analysis of the costimulatory receptor programmed death-1[J].Immunity,2004,20(3):337-347.
[9] Chen X,Fosco D,Kline DE,et al.PD-1 regulates extrathymic regulatory T-cell differentiation[J].Eur J Immunol,2014,44(9):2603-2616.
[10] Zak KM,Grudnik P,Guzik K,et al.Structural basis for small molecule targeting of the programmed death ligand 1(PD-L1)[J].Oncotarget,2016,7(21):30323-30335.
[11] Lee JY,Lee HT,Shin W,et al.Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy[J].Nat Commun,2016,7:13354.
[12] Shi JY,Zhang HY,Chen GY.Research progress of PD-L1/PD-1 pathway in solid tumors[J].China Medical Herald,2015,12(10):47-50.
[13] Takashima Y,Kawaguchi A,Kanayama T,et al.Correlation between lower balance of Th2 helper T-cells and expression of PD-L1/PD-1 axis genes enables prognostic prediction in patients with glioblastoma[J].Oncotarget,2018,9(27):19065-19078.
[14] Liu S,Chen S,Yuan W,et al.PD-1/PD-L1 interaction up-regulates MDR1/P-gp expression in breast cancer cells via PI3K/AKT and MAPK/ERK pathways[J].Oncotarget,2017,8(59):99901-99912.
[15] Gianchecchi E,Delfino DV,Fierabracci A.Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity[J].Autoimmun Rev,2013,12(11):1091-1100.
[16] Drakes ML,Mehrotra S,Aldulescu M,et al.Stratification of ovarian tumor pathology by expression of programmed cell death-1(PD-1) and PD-ligand-1(PD-L1) in ovarian cancer[J].J Ovarian Res,2018,11(1):1-11.
[17] Wehkamp U,Stern S,Krüger S,et al.Co-expression of NGF and PD-L1 on tumor-associated immune cells in the microenvironment of Merkel cell carcinoma[J].J Cancer Res Clin Oncol,2018,1:1-8.
[18] Schneider S,Kadletz L,Wiebringhaus R,et al.PD-1 and PD-L1 expression in HNSCC primary cancer and related lymph node metastasis-impact on clinical outcome[J].Histopathology,2018,2018(1):13646.
[19] Thar Min AK,Okayama H,Saito M,et al.Epithelial-mesenchymal transition-converted tumor cells can induce T-cell apoptosis through upregulation of programmed death ligand 1 expression in esophageal squamous cell carcinoma[J].Cancer Med,2018,7(7):3321-3330.
[20] Wang Y,Wang H,Zhao Q,et al.PD-L1 induces epithelial-to-mesenchymal transition via activating SREBP-1c in renal cell carcinoma[J].Med Oncol,2015,32(8):212.
[21] Cao Y,Zhang L,Kamimura Y,et al.B7-H1 overexpression regulates epithelial-mesenchymal transition and accelerates in skin[J].Cancer Res,2011,71(4):1235-1243.
[22] Liu B,Arakawa Y,Yokogawa R,et al.PD-1/PD-L1 expression in a series of intracranial germinoma and its association with Foxp3+ and CD8+ infiltrating lymphocytes[J].PLoS One,2018,13(4):e0194594.
[23] Deng C,Li Z,Guo S,et al.Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma[J].Oncoimmunology,2016,6(2):e1269047.
[24] Nomi T,Sho M,Akahori T,et al.Clinical significance and therapeutic potential of the programmed death/1 ligand/programmed death-1 pathway in human pancreatic cancer[J].Clin Cancer Res,2007,13(7):2151-2157.
[25] Hitzler M,Majdic O,Heine G,et al.Human Langerhans cells control Th cells via programmed death-ligand 1 in response to bacterial stimuli and nickel-induced contact allergy[J].PLoS One,2012,7(10):e46776.
[26] Zhong AY.Regulatory role of the PD-1/PD-L1 signaling pathway in Treg cells in lung cancer[D].Suzhou:Suzhou university,2016.
[27] Jiang L,Tang C,Gong Y,et al.PD-1/PD-L1 regulates Treg differentiation in pregnancy-induced hypertension[J].Braz J Med Biol Res,2018,51(8):e7334.
[28] Francisco LM,Salinas VH,Brown KE,et al.PD-L1 regulates the development,maintenance,and function of induced regulatory T cells[J].J Exp Med,2009,206(13):3015-3029.
[29] Zhao L,Li C,Liu F,et al.A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/Akt/mTOR signaling pathway[J].Onco Targets Ther,2017,10:2115-2126.
[30] Park HJ,Park JS,Jeong YH,et al.PD-1 upregulated on regulatory T cells during chronic virus infection enhances the suppression of CD8+ T cell immune response via the interaction with PD-L1 expressed on CD8+ T cells[J].J Immunol,2015,194(12):5801-5811.
[31] Chiu YM,Tsai CL,Kao JT,et al.PD-1 and PD-L1 up-regulation promotes T-cell apoptosis in gastric adenocarcinoma[J].Anticancer Res,2018,38(4):2069-2078.
[32] Shi F,Shi M,Zeng Z,et al.PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients[J].Int J Cancer,2011,128(4):887-896.
[33] Dong H,Strome SE,Salomao DR,et al.Tumor-associated B7H1 promotes T-cell apoptosis:A potential mahcanism of immune evasion[J].Nat Med,2002,8(8):4661-4665.
[34] Watanabe T,Bertoletti A,Tanoto TA.PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection[J].J Viral Hepat,2010,17(7):453-458.
[35] Duraiswamy J,Freeman GJ,Coukos G.Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer[J].Cancer Res,2013,73(23):69000-69012.
[36] Chen D,Tang P,Liu L,et al.Bone marrow-derived mesenchymal stem cells promote cell proliferation of multiple myeloma through inhibiting T cell immune responses via PD-1/PD-L1 pathway[J].Cell Cycle,2018,2018:1-10.
[37] Que Y,Xiao W,Guan YX,et al.PD-L1 Expression is associated with FOXP3+ regulatory T-cell infiltration of soft tissue sarcoma and poor patient prognosis[J].J Cancer,2017,8(11):2018-2025.
[38] Tai H,Yang Q,Wu Z,et al.PD-L1 expression predicts a distinct prognosis in Krukenberg tumor with corresponding origins[J].J Immunol Res,2018,2018:9485285.
[39] Salhab M,Migdady Y,Donahue M,et al.Immunohistochemical expression and prognostic value of PD-L1 in Extrapulmonary small cell carcinoma:A single institution experience[J].J Immunother Cancer,2018,6(1):42.
[40] Sheng Z,Zhu X,Sun Y,et al.The efficacy of anti-PD-1/PD-L1 therapy and its comparison with EGFR-TKIs for advanced non-small cell lung cancer[J].Oncotarget,2017,8(34):57826-57835.
[41] Konishi J,Yamazaki K,Azuma M,et al.B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression[J].Clin Cancer Res,2004,10(15):5094-5100.
[42] Mkrtichyan M,Najjar YG,Raulfs EC,et al.Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms[J].Eur J Immunol,2011,41(10):2977-2986.