Guo Jingjing, Mu Di, Han Ying
National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medicial University Cancer Institute and Hospital, Tianjin 300060, China.
Department of Biotherapy, Tianjin Medicial University Cancer Institute and Hospital, Tianjin 300060, China.
Zhongguo Fei Ai Za Zhi. 2021 Jan 20;24(1):49-55. doi: 10.3779/j.issn.1009-3419.2020.102.49.
Programmed cell death receptor 1 (PD-1) is a membrance-spanning protein mostly expressed in the T cell, and combines with programmed cell death ligand 1 (PD-L1) in the targeting cell. When binding to the ligand on tumor cells, PD-1 as an immunosuppressive molecule, can inhibit the immune function of T cells, thus tumor immune escape. For example, depletion of peripheral effector T cell and accelerate the transformation of effector T cells into regulator T cells. To solve this problem, PD-1 antibody is used to bind to PD-1 on T cells to inhibit the interaction between PD-1 on the T cells and PD-L1 on the tumor cells so that it can restore the function of T cells to kill tumor cell. PD-1 antibodies, such as Nivolumab and Pembrolizumb, are approved as a first-line treatment for advanced non-small cell lung cell cancer. However, due to the interaction of tumor cells, T cells and cytokines, some patients developed drug resistance which reduces the efficacy of immunotherapy. Hence, how to overcome resistance has become a urgent problem. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex and the only known molecular receptor of immunoregulatory drugs, has been found to reverse PD-1 antibody resistance by binding to CRBN regulatory agents (CMS), exert T cell immune function by regulating proliferation, activation and metabolism of T cell. In this paper, the mechanism of down-regulation of T cells leading to resistance of PD-1 antibody in lung cancer, the mechanism of CRBN regulating T cells, and research progress of CRBN regulator in the treatment of lung cancer were reviewed. .
程序性细胞死亡受体1（PD-1）是一种主要在T细胞中表达的跨膜蛋白，它与靶细胞中的程序性细胞死亡配体1（PD-L1）结合。当与肿瘤细胞上的配体结合时，PD-1作为一种免疫抑制分子，可抑制T细胞的免疫功能，从而导致肿瘤免疫逃逸。例如，使外周效应T细胞耗竭，并加速效应T细胞向调节性T细胞的转变。为了解决这个问题，人们使用PD-1抗体与T细胞上的PD-1结合，以抑制T细胞上的PD-1与肿瘤细胞上的PD-L1之间的相互作用，从而恢复T细胞杀伤肿瘤细胞的功能。PD-1抗体，如纳武单抗和派姆单抗，已被批准作为晚期非小细胞肺癌的一线治疗药物。然而，由于肿瘤细胞、T细胞和细胞因子之间的相互作用，一些患者产生了耐药性，降低了免疫治疗的疗效。因此，如何克服耐药性已成为一个紧迫的问题。cereblon（CRBN）是DDB1- Culllin-RING E3泛素连接酶复合物的底物受体，也是免疫调节药物唯一已知的分子受体，已发现它通过与CRBN调节剂（CMS）结合来逆转PD-1抗体耐药性，通过调节T细胞的增殖、活化和代谢来发挥T细胞免疫功能。本文综述了肺癌中T细胞下调导致PD-1抗体耐药的机制、CRBN调节T细胞的机制以及CRBN调节剂在肺癌治疗中的研究进展。
