PD-L1表达调控研究进展
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摘要
PD-1/PD-L1信号通路是肿瘤免疫逃逸主要机制之一。通过单克隆抗体与配体或受体结合阻断PD-1和PD-L1之间的相互作用在如黑色素瘤、非小细胞肺癌等多种肿瘤患者中疗效显著,但是只对部分患者有效。已开展的临床研究发现患者肿瘤部位的PD-L1表达量可能与PD-1/PD-L1抑制剂的疗效及预后相关。因此,深入研究PD-L1的表达调控机制有利于为肿瘤免疫治疗提供新的思路和潜在靶点,改进PD-1/PD-L1抑制剂的疗效。全文将PD-L1表达调控分为转录水平和转录后水平,对近几年PD-L1表达调控研究进展作一综述。
PD-1/PD-L1 signaling pathway is one of the main mechanisms of tumor immune escape. Monoclonal antibodies which block the interaction between PD-1 and PD-L1 have shown promising outcomes in various cancers,such as melanoma,non-small-cell lung cancer. But only a proportion of patients responds to the therapy. PD-L1 expression seems to correlate with the efficacy of PD-1/PD-L1 inhibitors and the clinical outcomes. Understanding the regulation mechanisms of PD-L1 would provide the new targets for tumor immunotherapy and improve the efficacy of PD-1/PD-L1 inhibitors.
PD-1/PD-L1 signaling pathway is one of the main mechanisms of tumor immune escape. Monoclonal antibodies which block the interaction between PD-1 and PD-L1 have shown promising outcomes in various cancers,such as melanoma,non-small-cell lung cancer. But only a proportion of patients responds to the therapy. PD-L1 expression seems to correlate with the efficacy of PD-1/PD-L1 inhibitors and the clinical outcomes. Understanding the regulation mechanisms of PD-L1 would provide the new targets for tumor immunotherapy and improve the efficacy of PD-1/PD-L1 inhibitors.
引文
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[4]Keir Mary E,Butte Manish J,Freeman Gordon J,et al.PD-1 and its ligands in tolerance and immunity[J].Annu Rev Immunol,2008,26:677-704.
[5]Boussiotis Vassiliki A.Molecular and biochemical aspects of the PD-1 checkpoint pathway[J].N Engl J Med,2016,375(18):1767-1778.
[6]Gordon Sydney R,Maute Roy L,Dulken Ben W,et al.PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity[J].Nature,2017,545(7655):495-499.
[7]Topalian Suzanne L,Taube Janis M,Anders Robert A,et al.Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy[J].Nat Rev Cancer,2016,16(5):275-287.
[8]Zou Weiping,Wolchok Jedd D,Chen Lieping.PD-L1(B7-H1)and PD-1 pathway blockade for cancer therapy:mechanisms,response biomarkers,and combinations[J].Sci Transl Med,2016,8(328):328rv4.
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[10]Akbay Esra A,Koyama Shohei,Carretero Julian,et al.Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors[J].Cancer Discov,2013,3(12):1355-1363.
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[13]Monypenny James,Milewicz Hanna,Flores-Borja Fabian,et al.ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation[J].Cell Rep,2018,24(3):630-641.
[14]Parsa Andrew T,Waldron James S,Panner Amith et al.Loss of tumor suppressor PTEN function increases B7-H1expression and immunoresistance in glioma[J].Nat Med,2007,13(1):84-88.
[15]Mittendorf Elizabeth A,Philips Anne V,Meric-Bernstam Funda,et al.PD-L1 expression in triple-negative breast cancer[J].Cancer Immunol Res,2014,2(4):361-370.
[16]Prestipino Alessandro,Emhardt Alica J,Aumann Konrad,et al.Oncogenic JAK2 causes PD-L1 expression,mediating immune escape in myeloproliferative neoplasms[J].Sci Transl Med,2018,10(429):pii:eaam7729.
[17]Xu LJ,Chen XD,Shen MJ,et al.Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels[J].Mol Oncol,2018,12(3):269-286.
[18]Zhang XH,Zeng YY,Qu QX,et al.PD-L1 induced by IFN-γfrom tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer[J].Int J Clin Oncol,2017,22(6):1026-1033.
[19]Qian YG,Deng JF,Geng L,et al.TLR4 signaling induces B7-H1 expression through MAPK pathways in bladder cancer cells[J].Cancer Invest,2008,26(8):816-821.
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[21]Casey Stephanie C,Tong Ling,Li Yulin,et al.MYC regulates the antitumor immune response through CD47 and PD-L1[J].Science,2016,352(6282):227-231.
[22]Marzec Michal,Zhang Q,Goradia Ami,et al.Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274(PD-L1,B7-H1)[J].Proc Natl Acad Sci USA,2008,105(52):20852-20857.
[23]Bu LL,Yu GT,Wu L,et al.STAT3 induces immunosuppression by upregulating PD-1/PD-L1 in HNSCC[J].JDent Res,2017,96(9):1027-1034.
[24]Gowrishankar Kavitha,Gunatilake Dilini,Gallagher Stuart J,et al.Inducible but not constitutive expression of PD-L1in human melanoma cells is dependent on activation of NF-κB[J].PLoS One,2015,10(4):e0123410.
[25]Xue JL,Chen CH,Qi ML,et al.Type Iγphosphatidylinositol phosphate kinase regulates PD-L1 ex pression by activating NF-κB[J].Oncotarget,2017,8(26):42414-42427.
[26]Bi XW,Wang H,Zhang WW,et al.PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma[J].J Hematol Oncol,2016,9(1):109.
[27]Fang WF,Zhang JW,Hong SD,et al.EBV-driven LMP1and IFN-γup-regulate PD-L1 in nasopharyngeal carcinoma:implications for oncotargeted therapy[J].Oncotarget,2014,5(23):12189-12202.
[28]Noman Muhammad Zaeem,Chouaib Salem.Targeting hypoxia at the forefront of anticancer immune responses[J].Oncoimmunology,2014,3(12):e954463.
[29]Barsoum Ivraym B,Smallwood Chelsea A,Siemens DRobert,et al.A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells[J].Cancer Res,2014,74(3):665-674.
[30]Zhu Hengrui,Bengsch Fee,Svoronos Nikolaos,et al.BETbromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression[J].Cell Rep,2016,16(11):2829-2837.
[31]Filippakopoulos Panagis,Knapp Stefan.Targeting bromodomains:epigenetic readers of lysine acetylation[J].Nat Rev Drug Discov,2014,13(5):337-356.
[32]Hogg Simon J,Vervoort Stephin J,Deswal Sumit,et al.BET-bromodomain inhibitors engage the host immune system and regulate expression of the immune checkpoint ligand PD-L1[J].Cell Rep,2017,18(9):2162-2174.
[33]Wang J,Jia Y,Zhao S,et al.BIN1 reverses PD-L1-mediated immune escape by inactivating the c-MYC and EGFR/MAPK signaling pathways in non-small cell lung cancer[J].Oncogene,2017,36(45):6235-6243.
[34]Dorand R Dixon,Nthale Joseph,Myers Jay T,et al.Cdk5disruption attenuates tumor PD-L1 expression and promotes antitumor immunity[J].Science,2016,353(6297):399-403.
[35]Mouw Kent W,Konstantinopoulos Panagiotis A.From checkpoint to checkpoint:DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation[J].Br J Cancer,2018,118(7):933-935.
[36]Sato Hiro,Niimi Atsuko,Yasuhara Takaaki,et al.DNAdouble-strand break repair pathway regulates PD-L1 expression in cancer cells[J].Nat Commun,2017,8(1):1751.
[37]Wrangle John,Wang Wei,Koch Alexander,et al.Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine[J].Oncotarget,2013,4(11):2067-2079.
[38]Woods David M,SodréAndressa L,Villagra Alejandro et al.HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade[J].Cancer Immunol Res,2015,3(12):1375-1385.
[39]Burr Marian L,Sparbier Christina E,Chan Yih-Chih,et al.CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity[J].Nature,2017,549(7670):101-105.
[40]Mezzadra Riccardo,Sun Chong,Jae Lucas T,et al.Identification of CMTM6 and CMTM4 as PD-L1 protein regulators[J].Nature,2017,549(7670):106-110.
[41]Zhang JF,Bu X,Wang HZ,et al.Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance[J].Nature,2018,553(7686):91-95.
[42]Goel Shom,DeCristo Molly J,Watt April C,et al.CDK4/6inhibition triggers anti-tumour immunity[J].Nature,2017,548(7668):471-475.
[43]Lim Seung-Oe,Li Chia-Wei,Xia Weiya,et al.Deubiquitination and stabilization of PD-L1 by CSN5[J].Cancer Cell,2016,30(6):925-939.
[44]Herbst Roy S,Soria Jean-Charles,Kowanetz Marcin,et al.Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients[J].Nature,2014,515(7528):563-567.
[45]Diaz Luis A,Le Dung T.PD-1 blockade in tumors with mismatch-repair deficiency[J].N Engl J Med,2015,373(20):1979.
[46]Coelho Matthew A,de CarnéTrécesson Sophie,Rana Sareena,et al.Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA[J].Immunity,2017,47(6):1083-1099.
[47]Wu L,Chen Z,Zhang J,et al.Effect of miR-513a-5p on etoposide-stimulating B7-H1 expression in retinoblastoma cells[J].J Huazhong Univ Sci Technol Med Sci,2012,32(4):601-606.
[48]Cortez Maria Angelica,Ivan Cristina,Valdecanas David,et al.PDL1 regulation by p53 via miR-34.[J].J Natl Cancer Inst,2016,108(1):djv303-djv303.
[49]Wang QS,Lin W,Tang XQ,et al.The roles of microRNAs in regulating the expression of PD-1/PD-L1 immune checkpoint[J].Int J Mol Sci,2017,18(12):2540.
[50]Wargo Jennifer A,Cooper Zachary A,Flaherty Keith T.U-niverses collide:combining immunotherapy with targeted therapy for cancer[J].Cancer Discov,2014,4(12):1377-1386.
[51]Gettinger Scott,Hellmann Matthew D,Chow Laura QM,et al.Nivolumab plus erlotinib in patients with EGFR-Mutant advanced NSCLC[J].J Thorac Oncol,2018,pii:S1556-0864(18)30628-2.
[2]Homet Moreno B,Ribas A.Anti-programmed cell death protein-1/ligand-1 therapy in different cancers[J].Br JCancer,2015,112(9):1421-1427.
[3]Wang QQ,Liu F,Liu L.Prognostic significance of PD-L1in solid tumor:an updated meta-analysis[J].Medicine(Baltimore),2017,96(18):e6369.
[4]Keir Mary E,Butte Manish J,Freeman Gordon J,et al.PD-1 and its ligands in tolerance and immunity[J].Annu Rev Immunol,2008,26:677-704.
[5]Boussiotis Vassiliki A.Molecular and biochemical aspects of the PD-1 checkpoint pathway[J].N Engl J Med,2016,375(18):1767-1778.
[6]Gordon Sydney R,Maute Roy L,Dulken Ben W,et al.PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity[J].Nature,2017,545(7655):495-499.
[7]Topalian Suzanne L,Taube Janis M,Anders Robert A,et al.Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy[J].Nat Rev Cancer,2016,16(5):275-287.
[8]Zou Weiping,Wolchok Jedd D,Chen Lieping.PD-L1(B7-H1)and PD-1 pathway blockade for cancer therapy:mechanisms,response biomarkers,and combinations[J].Sci Transl Med,2016,8(328):328rv4.
[9]Ohaegbulam Kim C,Assal Amer,Lazar-Molnar Eszter,et al.Human cancer immunotherapy with antibodies to the PD-1and PD-L1 pathway[J].Trends Mol Med,2015,21(1):24-33.
[10]Akbay Esra A,Koyama Shohei,Carretero Julian,et al.Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors[J].Cancer Discov,2013,3(12):1355-1363.
[11]Chen N,Fang WF,Zhan JH,et al.Upregulation of PD-L1by EGFR activation mediates the immune escape in EGFR-driven NSCLC:implication for optional immune targeted therapy for NSCLC patients with EGFR mutation[J].J Thorac Oncol,2015,10(6):910-923.
[12]Ota Keiichi,Azuma Koichi,Kawahara Akihiko et al.Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer[J].Clin Cancer Res,2015,21(17):4014-4021.
[13]Monypenny James,Milewicz Hanna,Flores-Borja Fabian,et al.ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation[J].Cell Rep,2018,24(3):630-641.
[14]Parsa Andrew T,Waldron James S,Panner Amith et al.Loss of tumor suppressor PTEN function increases B7-H1expression and immunoresistance in glioma[J].Nat Med,2007,13(1):84-88.
[15]Mittendorf Elizabeth A,Philips Anne V,Meric-Bernstam Funda,et al.PD-L1 expression in triple-negative breast cancer[J].Cancer Immunol Res,2014,2(4):361-370.
[16]Prestipino Alessandro,Emhardt Alica J,Aumann Konrad,et al.Oncogenic JAK2 causes PD-L1 expression,mediating immune escape in myeloproliferative neoplasms[J].Sci Transl Med,2018,10(429):pii:eaam7729.
[17]Xu LJ,Chen XD,Shen MJ,et al.Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels[J].Mol Oncol,2018,12(3):269-286.
[18]Zhang XH,Zeng YY,Qu QX,et al.PD-L1 induced by IFN-γfrom tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer[J].Int J Clin Oncol,2017,22(6):1026-1033.
[19]Qian YG,Deng JF,Geng L,et al.TLR4 signaling induces B7-H1 expression through MAPK pathways in bladder cancer cells[J].Cancer Invest,2008,26(8):816-821.
[20].Jiang XF,Zhou J,Giobbie-Hurder Anita,et al.The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition[J].Clin Cancer Res,2013,19(3):598-609.
[21]Casey Stephanie C,Tong Ling,Li Yulin,et al.MYC regulates the antitumor immune response through CD47 and PD-L1[J].Science,2016,352(6282):227-231.
[22]Marzec Michal,Zhang Q,Goradia Ami,et al.Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274(PD-L1,B7-H1)[J].Proc Natl Acad Sci USA,2008,105(52):20852-20857.
[23]Bu LL,Yu GT,Wu L,et al.STAT3 induces immunosuppression by upregulating PD-1/PD-L1 in HNSCC[J].JDent Res,2017,96(9):1027-1034.
[24]Gowrishankar Kavitha,Gunatilake Dilini,Gallagher Stuart J,et al.Inducible but not constitutive expression of PD-L1in human melanoma cells is dependent on activation of NF-κB[J].PLoS One,2015,10(4):e0123410.
[25]Xue JL,Chen CH,Qi ML,et al.Type Iγphosphatidylinositol phosphate kinase regulates PD-L1 ex pression by activating NF-κB[J].Oncotarget,2017,8(26):42414-42427.
[26]Bi XW,Wang H,Zhang WW,et al.PD-L1 is upregulated by EBV-driven LMP1 through NF-κB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma[J].J Hematol Oncol,2016,9(1):109.
[27]Fang WF,Zhang JW,Hong SD,et al.EBV-driven LMP1and IFN-γup-regulate PD-L1 in nasopharyngeal carcinoma:implications for oncotargeted therapy[J].Oncotarget,2014,5(23):12189-12202.
[28]Noman Muhammad Zaeem,Chouaib Salem.Targeting hypoxia at the forefront of anticancer immune responses[J].Oncoimmunology,2014,3(12):e954463.
[29]Barsoum Ivraym B,Smallwood Chelsea A,Siemens DRobert,et al.A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells[J].Cancer Res,2014,74(3):665-674.
[30]Zhu Hengrui,Bengsch Fee,Svoronos Nikolaos,et al.BETbromodomain inhibition promotes anti-tumor immunity by suppressing PD-L1 expression[J].Cell Rep,2016,16(11):2829-2837.
[31]Filippakopoulos Panagis,Knapp Stefan.Targeting bromodomains:epigenetic readers of lysine acetylation[J].Nat Rev Drug Discov,2014,13(5):337-356.
[32]Hogg Simon J,Vervoort Stephin J,Deswal Sumit,et al.BET-bromodomain inhibitors engage the host immune system and regulate expression of the immune checkpoint ligand PD-L1[J].Cell Rep,2017,18(9):2162-2174.
[33]Wang J,Jia Y,Zhao S,et al.BIN1 reverses PD-L1-mediated immune escape by inactivating the c-MYC and EGFR/MAPK signaling pathways in non-small cell lung cancer[J].Oncogene,2017,36(45):6235-6243.
[34]Dorand R Dixon,Nthale Joseph,Myers Jay T,et al.Cdk5disruption attenuates tumor PD-L1 expression and promotes antitumor immunity[J].Science,2016,353(6297):399-403.
[35]Mouw Kent W,Konstantinopoulos Panagiotis A.From checkpoint to checkpoint:DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation[J].Br J Cancer,2018,118(7):933-935.
[36]Sato Hiro,Niimi Atsuko,Yasuhara Takaaki,et al.DNAdouble-strand break repair pathway regulates PD-L1 expression in cancer cells[J].Nat Commun,2017,8(1):1751.
[37]Wrangle John,Wang Wei,Koch Alexander,et al.Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine[J].Oncotarget,2013,4(11):2067-2079.
[38]Woods David M,SodréAndressa L,Villagra Alejandro et al.HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade[J].Cancer Immunol Res,2015,3(12):1375-1385.
[39]Burr Marian L,Sparbier Christina E,Chan Yih-Chih,et al.CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity[J].Nature,2017,549(7670):101-105.
[40]Mezzadra Riccardo,Sun Chong,Jae Lucas T,et al.Identification of CMTM6 and CMTM4 as PD-L1 protein regulators[J].Nature,2017,549(7670):106-110.
[41]Zhang JF,Bu X,Wang HZ,et al.Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance[J].Nature,2018,553(7686):91-95.
[42]Goel Shom,DeCristo Molly J,Watt April C,et al.CDK4/6inhibition triggers anti-tumour immunity[J].Nature,2017,548(7668):471-475.
[43]Lim Seung-Oe,Li Chia-Wei,Xia Weiya,et al.Deubiquitination and stabilization of PD-L1 by CSN5[J].Cancer Cell,2016,30(6):925-939.
[44]Herbst Roy S,Soria Jean-Charles,Kowanetz Marcin,et al.Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients[J].Nature,2014,515(7528):563-567.
[45]Diaz Luis A,Le Dung T.PD-1 blockade in tumors with mismatch-repair deficiency[J].N Engl J Med,2015,373(20):1979.
[46]Coelho Matthew A,de CarnéTrécesson Sophie,Rana Sareena,et al.Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA[J].Immunity,2017,47(6):1083-1099.
[47]Wu L,Chen Z,Zhang J,et al.Effect of miR-513a-5p on etoposide-stimulating B7-H1 expression in retinoblastoma cells[J].J Huazhong Univ Sci Technol Med Sci,2012,32(4):601-606.
[48]Cortez Maria Angelica,Ivan Cristina,Valdecanas David,et al.PDL1 regulation by p53 via miR-34.[J].J Natl Cancer Inst,2016,108(1):djv303-djv303.
[49]Wang QS,Lin W,Tang XQ,et al.The roles of microRNAs in regulating the expression of PD-1/PD-L1 immune checkpoint[J].Int J Mol Sci,2017,18(12):2540.
[50]Wargo Jennifer A,Cooper Zachary A,Flaherty Keith T.U-niverses collide:combining immunotherapy with targeted therapy for cancer[J].Cancer Discov,2014,4(12):1377-1386.
[51]Gettinger Scott,Hellmann Matthew D,Chow Laura QM,et al.Nivolumab plus erlotinib in patients with EGFR-Mutant advanced NSCLC[J].J Thorac Oncol,2018,pii:S1556-0864(18)30628-2.