Cereblon调节T细胞逆转PD-1抗体治疗肺癌耐药的研究进展

Research Progress on the Mechanism and Clinical Data of Cereblon in Reversing the Resistance of Lung Cancer to PD-1 Antibody by T cells

程序性细胞死亡受体1(programmed cell death receptor 1, PD-1)是一种跨膜蛋白,主要表达于T细胞,并与靶细胞上的PD-1配体,即细胞程序性死亡配体1(programmed cell death ligand 1, PD-L1)结合。PD-1作为一种免疫抑制分子,当PD-1与肿瘤细胞上的配体PD-L1结合时,抑制了T细胞的免疫功能,从而发生肿瘤的免疫逃逸,如外周效应T细胞的耗竭导致效应T细胞向调节性T细胞(regulatory T cells, Tregs)转化。为解决这一问题,利用PD-1抗体与T细胞上的PD-1结合,从而抑制T细胞表面的PD-1与肿瘤细胞表面的PD-L1相互作用,进而恢复T细胞杀伤肿瘤细胞的功能。以Nivolumab和Pembrolizumab为代表的PD-1抗体现已被批准用于晚期非小细胞肺癌的一线治疗。但在部分患者中出现了由于肿瘤细胞、T细胞及细胞因子的相互作用导致的耐药,降低了免疫治疗的疗效。因此,如何克服患者的耐药成为了当前待解决的主要问题。研究发现,Cereblon(CRBN)作为DDB1泛素环E3泛素连接酶复合物的底物受体及免疫调节药物唯一已知的结合受体,与CRBN调节剂(cereblon modulatory agents, CMs)结合可以通过上调T细胞的增殖、激活和代谢,发挥T细胞的免疫功能从而逆转PD-1抗体耐药。本文就T细胞的下调导致PD-1抗体治疗肺癌耐药的机制、CRBN调节T细胞的机制及CRBN调节剂治疗肺癌的研究进展进行综述。

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.