程序性死亡受体-1(programmed death receptor-1,PD-1)锚定在抗原特异性细胞毒性T淋巴细胞(cytotoxic T lymphocytes,CTLs)的细胞膜上,其特异性配体程序性死亡–配体1(programmed death-ligand 1,PD-L1)是一种分子量约为40 kDa的I型跨...程序性死亡受体-1(programmed death receptor-1,PD-1)锚定在抗原特异性细胞毒性T淋巴细胞(cytotoxic T lymphocytes,CTLs)的细胞膜上,其特异性配体程序性死亡–配体1(programmed death-ligand 1,PD-L1)是一种分子量约为40 kDa的I型跨膜蛋白,在正常组织中广泛表达。在正常生理条件下,PD-1和PD-L1之间的胞外结合通过抑制CTLs活性从而阻止自身免疫疾病的发生。然而,PD-L1在黑色素瘤、肺癌、肾细胞癌等恶性肿瘤中的异常上调表达通过促进PD-1/PD-L1介导的CTLs失活导致癌细胞逃避免疫监控。近年来,相关研究分别从基因扩增、染色质修饰、转录与转录后修饰、翻译与翻译后修饰等角度阐述了PD-L1表达调控的分子机制。同时,针对PD-1/PD-L1轴的免疫检查点阻断治疗在多种恶性肿瘤的临床治疗中展现出了较好的疗效。该文系统总结了近年来癌细胞中的PD-L1表达调控机制研究领域的重要成果,并在此基础上展望了针对PD-1/PD-L1轴的肿瘤免疫治疗的应用前景。展开更多
During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is...During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is immune-suppression regulated by programmed cell death-1 or its ligand 1(PD-1/PD-L1),which makes PD-1/PD-L1 blockadea promising target of cancer immune-therapy.Tumors could suppress immuno-response of T cells by activating PD-1/PD-L1 signaling pathway.Therefore,inhibiting the interaction between PD-1 and PD-L1 could reconstitute the enduring antitumor immunity in the tumor microenvironment via enhancing the T-cell response,there after augmenting the endogenous antitumor force of the immune system.Along these lines,inhibitors of PD-1/PD-L1 has been applied in multiple clinical trials against various types of tumors.Recent studies indicated that PD-1/PD-L1 blockade have demonstrated high efficacy and safety against melanoma,lung,kidney and several other solid tumors,as well as hematological malignancies.Nevertheless,the efficacy of this checkpoint blockade approach is not universal.Some investigation suggested that lack of responses to anti-PD-1/PD-L1 therapy of patients without PD-1/PD-L1 over-expression was expected.In this review,we summarize the history and current understanding of multiple intrinsic and extrinsic mechanisms via which PD-1/PD-L1 is regulated and research advances in preclinical/clinical aspects of PD-1/PD-L1,as well as significance and perspectives regarding the PD-1/PD-L1 blockade in immune-antitumor therapy.展开更多
文摘程序性死亡受体-1(programmed death receptor-1,PD-1)锚定在抗原特异性细胞毒性T淋巴细胞(cytotoxic T lymphocytes,CTLs)的细胞膜上,其特异性配体程序性死亡–配体1(programmed death-ligand 1,PD-L1)是一种分子量约为40 kDa的I型跨膜蛋白,在正常组织中广泛表达。在正常生理条件下,PD-1和PD-L1之间的胞外结合通过抑制CTLs活性从而阻止自身免疫疾病的发生。然而,PD-L1在黑色素瘤、肺癌、肾细胞癌等恶性肿瘤中的异常上调表达通过促进PD-1/PD-L1介导的CTLs失活导致癌细胞逃避免疫监控。近年来,相关研究分别从基因扩增、染色质修饰、转录与转录后修饰、翻译与翻译后修饰等角度阐述了PD-L1表达调控的分子机制。同时,针对PD-1/PD-L1轴的免疫检查点阻断治疗在多种恶性肿瘤的临床治疗中展现出了较好的疗效。该文系统总结了近年来癌细胞中的PD-L1表达调控机制研究领域的重要成果,并在此基础上展望了针对PD-1/PD-L1轴的肿瘤免疫治疗的应用前景。
文摘During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is immune-suppression regulated by programmed cell death-1 or its ligand 1(PD-1/PD-L1),which makes PD-1/PD-L1 blockadea promising target of cancer immune-therapy.Tumors could suppress immuno-response of T cells by activating PD-1/PD-L1 signaling pathway.Therefore,inhibiting the interaction between PD-1 and PD-L1 could reconstitute the enduring antitumor immunity in the tumor microenvironment via enhancing the T-cell response,there after augmenting the endogenous antitumor force of the immune system.Along these lines,inhibitors of PD-1/PD-L1 has been applied in multiple clinical trials against various types of tumors.Recent studies indicated that PD-1/PD-L1 blockade have demonstrated high efficacy and safety against melanoma,lung,kidney and several other solid tumors,as well as hematological malignancies.Nevertheless,the efficacy of this checkpoint blockade approach is not universal.Some investigation suggested that lack of responses to anti-PD-1/PD-L1 therapy of patients without PD-1/PD-L1 over-expression was expected.In this review,we summarize the history and current understanding of multiple intrinsic and extrinsic mechanisms via which PD-1/PD-L1 is regulated and research advances in preclinical/clinical aspects of PD-1/PD-L1,as well as significance and perspectives regarding the PD-1/PD-L1 blockade in immune-antitumor therapy.
