Innate Immune Checkpoint Inhibitors: The Next Breakthrough in Medical Oncology?

While immunotherapy has revolutionized the treatment of many types of advanced cancer, most patients still do not derive benefit. The currently available immune checkpoint inhibitors target the adaptive immune system, generating a T cell anti-tumor response. However, an anti-tumor immune response depends on a complex interplay of both innate and adaptive immune cells. The innate immune system is a promising new target, and innate immune checkpoint inhibitors can disrupt inhibitory interactions (“don’t eat me” signals) between tumor and both phagocytes and natural killer cells. The checkpoint inhibitor may also provide a stimulatory interaction (“eat me” signal), or this can be achieved through use of combination therapy. This generates anti-tumor effector functions including phagocytosis, natural cytotoxicity, antibody-dependent effects, and synergistic activation of the adaptive immune system via antigen presentation. This is a rapidly expanding area of drug development, either alone or in combination (with anti-cancer antibodies or adaptive immune checkpoint inhibitors). Here, we comprehensively review the mechanism of action and up-to-date solid tumor clinical trial data of the drugs targeting phagocytosis checkpoints (SIRPα/CD47, LILRB1/MHC-I, and LILRB2/MHC-I) and natural killer cell checkpoints (TIGIT/CD112 + CD155, PVRIG/CD112, KIRs/MHC-I, and NKG2A-CD94/HLA-E). Innate immune checkpoint inhibitors could once again revolutionize immune-based cancer therapies.

虽然免疫疗法已经彻底改变了许多类型晚期癌症的治疗方式，但大多数患者仍然没有受益。目前可用的免疫检查点抑制剂针对适应性免疫系统，产生T细胞抗肿瘤反应。然而，抗肿瘤免疫反应依赖于先天性免疫细胞和适应性免疫细胞之间复杂的相互作用。先天性免疫系统是一个有前景的新靶点，先天性免疫检查点抑制剂可以破坏肿瘤与吞噬细胞和自然杀伤细胞之间的抑制性相互作用（“不要吃我”信号）。检查点抑制剂也可能提供刺激性相互作用（“吃我”信号），或者这可以通过联合疗法来实现。这会产生抗肿瘤效应功能，包括吞噬作用、自然细胞毒性、抗体依赖效应，以及通过抗原呈递对适应性免疫系统的协同激活。这是一个药物研发迅速扩展的领域，无论是单独使用还是联合使用（与抗癌抗体或适应性免疫检查点抑制剂联合）。在此，我们全面综述了针对吞噬作用检查点（SIRPα/CD47、LILRB1/MHC - I和LILRB2/MHC - I）以及自然杀伤细胞检查点（TIGIT/CD112 + CD155、PVRIG/CD112、KIRs/MHC - I和NKG2A - CD94/HLA - E）的药物的作用机制和最新的实体瘤临床试验数据。先天性免疫检查点抑制剂可能再次彻底改变基于免疫的癌症治疗方法。