免疫检查点LAG-3在肿瘤中的研究进展
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摘要
免疫检查点抑制剂治疗是目前研究最为充分的免疫疗法之一,其基本原理即应用免疫检查点抑制剂阻断抑制信号的传递,刺激细胞毒性T淋巴细胞(CTL)的活化,诱导T淋巴细胞的抗肿瘤效应。淋巴细胞激活基因-3(LAG-3)作为免疫检查点家族的一员,是一种对T细胞功能有着多种生物学效应的抑制性分子,在多种类型的肿瘤浸润淋巴细胞(TIL)中高表达,参与肿瘤的免疫逃逸机制。因此,LAG-3可作为肿瘤预后的指标以及肿瘤治疗的靶点。本文对LAG-3在肿瘤中表达及功能的研究进展作一综述,并探讨LAG-3在肿瘤临床治疗上的应用前景。
Immune checkpoint inhibition,as a kind of adequately studied immunotherapy,is based on the blocking of passing inhibiting signals,excitation the CTL and inducing T lymphocyte to produce anti-tumor effect. LAG-3 is a kind of inhibitory molecule with multiple biological effects which is fond as a member of the immune checkpoint family. It has a high expression in the tumor infiltrating lymphocytes of many kinds of tumor tissues performing the tumor immune escape. Thus,we can conclude that LAG-3 will act as an important indicator in the prognosis and therapy of tumor. This review will talk about the expression and function of LAG-3 in tumor and how it is used in therapy.
Immune checkpoint inhibition,as a kind of adequately studied immunotherapy,is based on the blocking of passing inhibiting signals,excitation the CTL and inducing T lymphocyte to produce anti-tumor effect. LAG-3 is a kind of inhibitory molecule with multiple biological effects which is fond as a member of the immune checkpoint family. It has a high expression in the tumor infiltrating lymphocytes of many kinds of tumor tissues performing the tumor immune escape. Thus,we can conclude that LAG-3 will act as an important indicator in the prognosis and therapy of tumor. This review will talk about the expression and function of LAG-3 in tumor and how it is used in therapy.
引文
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[26]Huang RY,Francois A,Mcgray AR,et al.Compensatory upregulation of PD-1,LAG-3,and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer[J].Oncoimmunology,2017,6(1):e1249561.
[27]Ma QY,Huang DY,Zhang HJ,et al.Function and regulation of LAG3 on CD4+CD25-T cells in non-small cell lung cancer[J].Experimental Cell Research,2017,360(2):358-364.
[28]Hald SM,Rakaee M,Martinez I,et al.LAG-3 in non-smallcell lung cancer:Expression in primary tumors and metastatic lymph nodes is associated with improved survival[J].Clinical Lung Cancer,2017,19(3):249-259.
[29]Li FJ,Zhang Y,Jin GX,et al.Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8+,Tcell in HCC patients[J].Immunology Letters,2013,150(1-2):116-122.
[30]Camisaschi C,Casati C,Rini F,et al.LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+)regulatory T cells that are expanded at tumor sites[J].Journal of Immunology,2010,184(11):6545.
[31]Gagliani N,Magnani CF,Huber S,et al.Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells[J].Nature Medicine,2013,19(6):739-746.
[32]Chen J,Chen Z.The effect of immune microenvironment on the progression and prognosis of colorectal cancer[J].Medical Oncology,2014,31(8):1-8.
[33]Vasen HF,Watson P,Mecklin JP,et al.New clinical criteria for hereditary nonpolyposis colorectal cancer(HNPCC,Lynch syndrome)proposed by the International Collaborative Group on HNPCC[J].Gastroenterology,1999,116(6):1453.
[34]Sijmons RH,Hofstra RM.Clinical aspects of hereditary DNA mismatch repair gene mutations[J].DNA Repair,2015(38):155-162.
[35]Losa NL,Cruise M,Tam A,et al.The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints[J].Cancer Discovery,2015,3(S2):43-51.
[36]Becht E,Giraldo NA,Germain C,et al.Chapter four-immune contexture,immunoscore,and malignant cell molecular subgroups for prognostic and theranostic classifications of cancers[J].Advances in Immunology,2016,130:95-190.
[37]Park JH,Powell AG,Roxburgh CS,et al.Mismatch repair status in patients with primary operable colorectal cancer:Associations with the local and systemic tumour environment[J].Br J Cancer,2016,114(5):562-570.
[38]Sloan EA,Ring KL,Willis BC,et al.PD-L1 expression in mismatch repair-deficient endometrial carcinomas,including lynch syndrome-associated and mlh1 promoter hypermethylated tumors[J].American Journal of Surgical Pathology,2017,41(3):326.
[39]Sharma P,Allison JP.The future of immune checkpoint therapy[J].Science,2015,348(6230):56.
[40]Lee V,Murphy A,Le DT,et al.Mismatch repair deficiency and response to immune checkpoint blockade[J].Oncologist,2016,21(10):1200-1211.
[41]Legat A,Maby-El HH,Baumgaertner P,et al.Vaccination with LAG-3Ig(IMP321)and peptides induces specific CD4 and CD8T-cell responses in metastatic melanoma patients-report of a phase I/Ⅱaclinical trial[J].Clinical Cancer Research,2015,22(6):1330-1340.
[42]Brignone C,Gutierrez M,Mefti F,et al.First-line chemoimmunotherapy in metastatic breast carcinoma:Combination of paclitaxel and IMP321(LAG-3 Ig)enhances immune responses and antitumor activity[J].Journal of Translational Medicine,2010,8(1):71.
[43]Romano E,Michielin O,Voelter V,et al.MART-1 peptide vaccination plus IMP321(LAG-3Ig fusion protein)in patients receiving autologous PBMCs after lymphodepletion:Results of a phase Itrial[J].Journal of Translational Medicine,2014,12(1):97.
[2]Wherry EJ.T cell exhaustion[J].Nature Immunology,2011,12(6):492.
[3]Villadolid J,Amin A.Immune checkpoint inhibitors in clinical practice:Update on management of immune-related toxicities[J].Translational Lung Cancer Research,2015,4(5):560.
[4]Wang J,Yuan R,Song W,et al.PD-1,PD-L1(B7-H1)and tumor-site immune modulation therapy:The historical perspective[J].Journal of Hematology&Oncology,2017,10(1):34.
[5]Topalian SL,Hodi FS,Brahmer JR,et al.Safety,activity,and immune correlates of anti-PD-1 antibody in cancer[J].New England Journal of Medicine,2012,366(26):2443.
[6]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.
[7]Hamid O,Robert C,Daud A,et al.Safety and tumor responses with lambrolizumab(Anti-PD-1)in melanoma[J].New England Journal of Medicine,2013,369(2):134.
[8]Le DT,Durham JN,Smith KN,et al.Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade[J].Science,2017,357(6349):409.
[9]Fisher TS,Kamperschroer C,Oliphant T,et al.Targeting of 4-1BBby monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity[J].Cancer Immunology Immunotherapy Cii,2012,61(10):1721-1733.
[10]Curti BD,Kovacsovicsbankowski M,Morris N,et al.OX40 is a potent immune-stimulating target in late-stage cancer patients[J].Cancer Research,2013,73(24):7189-7198.
[11]Schaer DA,Hirschhorn-Cymerman D,Wolchok JD.Targeting tumor-necrosis factor receptor pathways for tumor immunotherapy[J].Journal for Immunotherapy of Cancer,2014,2(1):7.
[12]Jha V,Workman CJ,Mcgaha TL,et al.Lymphocyte Activation Gene-3(LAG-3)negatively regulates environmentally-induced autoimmunity[J].PLo S One,2014,9(8):e104484.
[13]Wang YW,Shi DB,Liu YM,et al.Aberrant expression of CD227is correlated with tumor characteristics and invasiveness of breast carcinoma[J].Journal of Cancer Research&Clinical Oncology,2014,140(8):1271-1281.
[14]Zhang YC,Guo LQ,Chen X,et al.The role of death receptor 3 in the biological behavior of hepatocellular carcinoma cells[J].Molecular Medicine Reports,2015,11(2):797-804.
[15]Goldberg MV,Drake CG.LAG-3 in cancer immunotherapy[J].Current Topics in Microbiology&Immunology,2011,344(1):269.
[16]Rivera SM,Padiernos RBC,Abella EA,et al.Molecular characterization of the lymphocyte activation gene-3(LAG-3,CD223)of swamp-and riverine-type water buffaloes(Bubalus bubalis)[J].Japanese Journal of Veterinary Research,2017,65(2):65-74.
[17]Triebel F,Jitsukawa S,Baixeras E,et al.LAG-3,a novel lymphocyte activation gene closely related to CD4[J].Journal of Experimental Medicine,1990,171(5):1393-1405.
[18]Huard B,Mastrangeli R,Prigent P,et al.Characterization of the major histocompatibility complex classⅡbinding site on LAG-3 protein[J].Proc Natl Acad Sci USA,1997,94(11):5744-5749.
[19]Fourcade J,Sun Z,Pagliano O,et al.CD8(+)T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLAand PD-1[J].Cancer Research,2012,72(4):887.
[20]Ezinne CC,Yoshimitsu M,White Y,et al.HTLV-1 specific CD8+T cell function augmented by blockade of 2B4/CD48 interaction in HTLV-1 infection[J].PLo S One,2014,9(2):e87631.
[21]Baitsch L,Legat A,Barba L,et al.Extended co-expression of inhibitory receptors by human CD8 T-cells depending on differentiation,antigen-specificity and anatomical localization[J].PLo SOne,2012,7(2):e30852.
[22]Baitsch L,Baumgaertner P,Devêvre E,et al.Exhaustion of tumor-specific CD8+T cells in metastases from melanoma patients[J].Journal of Clinical Investigation,2011,121(6):2350.
[23]Woo SR,Turnis ME,Goldberg MV,et al.Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T cell function to promote tumoral immune escape[J].Cancer Research,2012,72(4):917-927.
[24]Grosso JF,Kelleher CC,Harris TJ,et al.LAG-3 regulates CD8+T cell accumulation and effector function in murine self-and tumor-tolerance systems[J].Journal of Clinical Investigation,2007,117(11):3383-3392.
[25]Matsuzaki J,Gnjatic S,Mhawechfauceglia P,et al.Tumor-infiltrating NY-ESO-1-specific CD8+T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer[J].Proceedings of the National Academy of Sciences of the United States of America,2010,107(17):7875-7880.
[26]Huang RY,Francois A,Mcgray AR,et al.Compensatory upregulation of PD-1,LAG-3,and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer[J].Oncoimmunology,2017,6(1):e1249561.
[27]Ma QY,Huang DY,Zhang HJ,et al.Function and regulation of LAG3 on CD4+CD25-T cells in non-small cell lung cancer[J].Experimental Cell Research,2017,360(2):358-364.
[28]Hald SM,Rakaee M,Martinez I,et al.LAG-3 in non-smallcell lung cancer:Expression in primary tumors and metastatic lymph nodes is associated with improved survival[J].Clinical Lung Cancer,2017,19(3):249-259.
[29]Li FJ,Zhang Y,Jin GX,et al.Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8+,Tcell in HCC patients[J].Immunology Letters,2013,150(1-2):116-122.
[30]Camisaschi C,Casati C,Rini F,et al.LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+)regulatory T cells that are expanded at tumor sites[J].Journal of Immunology,2010,184(11):6545.
[31]Gagliani N,Magnani CF,Huber S,et al.Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells[J].Nature Medicine,2013,19(6):739-746.
[32]Chen J,Chen Z.The effect of immune microenvironment on the progression and prognosis of colorectal cancer[J].Medical Oncology,2014,31(8):1-8.
[33]Vasen HF,Watson P,Mecklin JP,et al.New clinical criteria for hereditary nonpolyposis colorectal cancer(HNPCC,Lynch syndrome)proposed by the International Collaborative Group on HNPCC[J].Gastroenterology,1999,116(6):1453.
[34]Sijmons RH,Hofstra RM.Clinical aspects of hereditary DNA mismatch repair gene mutations[J].DNA Repair,2015(38):155-162.
[35]Losa NL,Cruise M,Tam A,et al.The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints[J].Cancer Discovery,2015,3(S2):43-51.
[36]Becht E,Giraldo NA,Germain C,et al.Chapter four-immune contexture,immunoscore,and malignant cell molecular subgroups for prognostic and theranostic classifications of cancers[J].Advances in Immunology,2016,130:95-190.
[37]Park JH,Powell AG,Roxburgh CS,et al.Mismatch repair status in patients with primary operable colorectal cancer:Associations with the local and systemic tumour environment[J].Br J Cancer,2016,114(5):562-570.
[38]Sloan EA,Ring KL,Willis BC,et al.PD-L1 expression in mismatch repair-deficient endometrial carcinomas,including lynch syndrome-associated and mlh1 promoter hypermethylated tumors[J].American Journal of Surgical Pathology,2017,41(3):326.
[39]Sharma P,Allison JP.The future of immune checkpoint therapy[J].Science,2015,348(6230):56.
[40]Lee V,Murphy A,Le DT,et al.Mismatch repair deficiency and response to immune checkpoint blockade[J].Oncologist,2016,21(10):1200-1211.
[41]Legat A,Maby-El HH,Baumgaertner P,et al.Vaccination with LAG-3Ig(IMP321)and peptides induces specific CD4 and CD8T-cell responses in metastatic melanoma patients-report of a phase I/Ⅱaclinical trial[J].Clinical Cancer Research,2015,22(6):1330-1340.
[42]Brignone C,Gutierrez M,Mefti F,et al.First-line chemoimmunotherapy in metastatic breast carcinoma:Combination of paclitaxel and IMP321(LAG-3 Ig)enhances immune responses and antitumor activity[J].Journal of Translational Medicine,2010,8(1):71.
[43]Romano E,Michielin O,Voelter V,et al.MART-1 peptide vaccination plus IMP321(LAG-3Ig fusion protein)in patients receiving autologous PBMCs after lymphodepletion:Results of a phase Itrial[J].Journal of Translational Medicine,2014,12(1):97.