Song Mengjia, Chen Xinfeng, Wang Liping, Zhang Yi
Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Chin J Cancer Res. 2018 Apr;30(2):157-172. doi: 10.21147/j.issn.1000-9604.2018.02.01.
Programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L1) blockade has shown promising effects in cancer immunotherapy. Removing the so-called " brakes" on T cell immune responses by blocking the PD-1/PD-L1 check point should boost anti-tumor immunity and provide durable tumor regression for cancer patients. However, 30%-60% of patients show no response to PD-1/PD-L1 blockade. Thus, it is urgent to explore the underlying resistance mechanisms to improve sensitivity to anti-PD-1/PD-L1 therapy. We propose that the mechanisms promoting resistance mainly include T cell exclusion or exhaustion at the tumor site, immunosuppressive factors in the tumor microenvironment (TME), and a range of tumor-intrinsic factors. This review highlights the power of studying the cellular and molecular mechanisms of resistance to improve the rational design of combination therapeutic strategies that can be translated to the clinic. Here, we briefly discuss the development of PD-1/PD-L1 blockade agents and focus on the current issues and future prospects for potential combinatorial therapeutic strategies that include anti-PD-1/PD-L1 therapy, based upon the available preclinical and clinical data.
程序性细胞死亡蛋白1（PD-1）/程序性细胞死亡蛋白1配体（PD-L1）阻断在癌症免疫治疗中已显示出有前景的效果。通过阻断PD-1/PD-L1检查点来去除T细胞免疫反应上所谓的“刹车”，应该能增强抗肿瘤免疫力，并为癌症患者提供持久的肿瘤消退。然而，30%-60%的患者对PD-1/PD-L1阻断无反应。因此，迫切需要探索潜在的耐药机制以提高对抗PD-1/PD-L1治疗的敏感性。我们提出，促进耐药的机制主要包括肿瘤部位的T细胞排除或耗竭、肿瘤微环境（TME）中的免疫抑制因子以及一系列肿瘤内在因素。本综述强调了研究耐药的细胞和分子机制对于改进可转化至临床的联合治疗策略合理设计的作用。在此，我们简要讨论PD-1/PD-L1阻断剂的发展，并基于现有的临床前和临床数据，重点关注包括抗PD-1/PD-L1治疗在内的潜在联合治疗策略的当前问题和未来前景。
