ABSTRACT

Introduction: In the past few years, administrating monoclonal humanized antibodies, namely checkpoint inhibitors, against programmed cell death protein 1 (PD-1), and its ligand (PD-L1), has yielded reassuring tumor regression rates. Anti-PD-1/PD-L1 checkpoint inhibitors disrupt the engagement of PD-1 on T-cells and their ligands on tumor or other target cells and reactivate the tumor-specific T infiltrating lymphocytes (TILs), which are mostly in a state of anergy before the PD-1/PD-L1 blockade. However, a limited number of patients initially respond, and the others show a primary (innate) resistance. Moreover, the rate of relapse and tumor progression after a partial, or even complete response (secondary or acquired resistance) is relatively considerable.

Areas covered: This paper presents a comprehensive discussion on the mechanisms of primary and secondary resistance to PD-1/PD-L1 blockade. Loss of T-cell infiltration or T-cell exclusion, lack of PD-L1 or PD-1 expression, and also lack of tumor immunogenicity are among the most important mechanisms, and also biomarkers of resistance in patients undergoing PD-1/PD-L1 blockade. Several somatic mutations in tumors are known to be related to at least one of the resistance mechanisms.

Expert opinion: Identification of the novel resistance mechanisms suggests further combinatorial therapies to tackle primary and secondary resistance to PD-1/PD-L1 blockade.

摘要

简介：在过去的几年中，使用针对程序性细胞死亡蛋白 1 (PD-1) 及其配体 (PD-L1) 的单克隆人源化抗体，即检查点抑制剂，已经产生了令人放心的肿瘤消退率。抗 PD-1/PD-L1 检查点抑制剂破坏 PD-1 与 T 细胞及其配体与肿瘤或其他靶细胞的结合，并重新激活主要处于一种状态的肿瘤特异性 T 浸润淋巴细胞 (TIL) PD-1/PD-L1 阻断前的无反应性。然而，有限数量的患者最初有反应，而其他患者则表现出原发性（先天性）抵抗。此外，部分或什至完全反应（继发性或获得性耐药）后的复发率和肿瘤进展率相当可观。

涵盖的领域：本文全面讨论了对 PD-1/PD-L1 阻断的原发性和继发性耐药机制。T 细胞浸润或 T 细胞排斥的丧失、PD-L1 或 PD-1 表达的缺乏以及肿瘤免疫原性的缺乏是最重要的机制，也是接受 PD-1/PD- 治疗的患者的耐药生物标志物L1封锁。已知肿瘤中的几种体细胞突变与至少一种耐药机制有关。

专家意见：新耐药机制的鉴定表明进一步的组合疗法可以解决对 PD-1/PD-L1 阻断的原发性和继发性耐药。