免疫检查点抑制剂治疗非小细胞肺癌耐药机制研究进展

Research Progress of Drug Resistance Mechanisms of Immune Check-point Inhibitors in the Treatment of Non-Small Cell Lung Cancer

免疫是治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的治疗手段之一,但由于治疗期间的原发性和获得性耐药性,很大一部分患者无法从中受益。本文总结了针对程序性死亡受体1(programmed cell death protein 1,PD-1)/程序性死亡配体1(programmed cell death ligand 1,PD-L1)的免疫检查点抑制剂在NSCLC治疗中产生耐药性的关键机制最新研究,原发性耐药机制包括PD-L1表达异常及突变、T细胞本身的异常免疫和RAS、BRAF等信号通路因素导致免疫进化等,获得性耐药机制包括TIM-3、B7-H7、VISTA、LAG-3、CTLA-4、Siglec-15、TIGIT、BTLA等代偿性免疫检查点上调,以及记忆T细胞分化失败和肿瘤的免疫编辑等。我们还讨论了对PD-1/PD-L1阻断有效的条件及PD-1/PD-L1免疫治疗的抗肿瘤活性增强的策略,为提高免疫检查点抑制剂的临床疗效提供参考。

Immunotherapy is one of the treatments for advanced non-small cell lung cancer(NSCLC), but a large number of patients cannot benefit from it due to primary and acquired drug resistance during treatment. This review summarizes the latest research on the key mechanisms of resistance to PD-1/PD-L1 immune checkpoint inhibitors in the treatment of NSCLC. The primary resistance mechanisms include abnormal expression and mutation of PD-L1, abnormal immunity of T cells themselves, and immune evolution caused by RAS, BRAF and other signaling pathway factors. Acquired drug resistance mechanisms include tumor immunoediting, failed differentiation of memory T cells, and compensatory upregulation of immunity checkpoints such as TIM-3, B7-H7, VISTA, LAG-3, CTLA-4, Siglec-15, TIGIT and BTLA. We have also discussed the conditions that are effective for PD-1/PD-L1 blockade and strategies for potentiating the antitumor effect of PD-1/PD-L1 immunotherapy to provide evidence for improving the clinical efficacy of immune checkpoint inhibitors.