Division of Molecular and Cellular Oncology, Department of Radiation Oncology, University of California, Los Angles, Los Angeles, CA, USA.
Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
Nat Rev Immunol. 2020 Jan;20(1):25-39. doi: 10.1038/s41577-019-0218-4. Epub 2019 Sep 30.
'Immune checkpoint blockade' for cancer describes the use of therapeutic antibodies that disrupt negative immune regulatory checkpoints and unleash pre-existing antitumour immune responses. Antibodies targeting the checkpoint molecules cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1) and PD1 ligand 1 (PD-L1) have had early success in the clinic, which has led to approval by the US Food and Drug Administration of multiple agents in several cancer types. Yet, clinicians still have very limited tools to discriminate a priori patients who will and will not respond to treatment. This has fuelled a wave of research into the molecular mechanisms of tumour-intrinsic resistance to immune checkpoint blockade, leading to the rediscovery of biological processes critical to antitumour immunity, namely interferon signalling and antigen presentation. Other efforts have shed light on the immunological implications of canonical cancer signalling pathways, such as WNT-β-catenin signalling, cell cycle regulatory signalling, mitogen-activated protein kinase signalling and pathways activated by loss of the tumour suppressor phosphoinositide phosphatase PTEN. Here we review each of these molecular mechanisms of resistance and explore ongoing approaches to overcome resistance to immune checkpoint blockade and expand the spectrum of patients who can benefit from immune checkpoint blockade.
“免疫检查点阻断”治疗癌症是指利用治疗性抗体来破坏负性免疫调节检查点，并释放预先存在的抗肿瘤免疫反应。针对检查点分子细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）、程序性细胞死亡蛋白 1（PD1）和 PD1 配体 1（PD-L1）的抗体在临床上已取得早期成功，这促使美国食品和药物管理局（FDA）批准了多种癌症类型的多种药物。然而，临床医生仍然非常有限的工具来预先区分患者对治疗有反应和无反应的情况。这引发了一波针对肿瘤内在免疫检查点阻断耐药性的分子机制的研究，重新发现了对抗肿瘤免疫至关重要的生物学过程，即干扰素信号和抗原呈递。其他研究揭示了经典癌症信号通路（如 WNT-β-catenin 信号通路、细胞周期调控信号通路、丝裂原活化蛋白激酶信号通路以及肿瘤抑制因子磷酸肌醇磷酸酶 PTEN 缺失激活的通路）的免疫学意义。在这里，我们回顾了每种耐药的分子机制，并探讨了克服免疫检查点阻断耐药性和扩大能够从免疫检查点阻断中获益的患者范围的现有方法。
