Department of Pathology, Stanford University School of Medicine, Stanford, California 94304, USA; email:
Annu Rev Pathol. 2021 Jan 24;16:223-249. doi: 10.1146/annurev-pathol-042020-042741. Epub 2020 Nov 16.
Immune checkpoint inhibitors (ICIs) have made an indelible mark in the field of cancer immunotherapy. Starting with the approval of anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) for advanced-stage melanoma in 2011, ICIs-which now also include antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1)-quickly gained US Food and Drug Administration approval for the treatment of a wide array of cancer types, demonstrating unprecedented extension of patient survival. However, despite the success of ICIs, resistance to these agents restricts the number of patients able to achieve durable responses, and immune-related adverse events complicate treatment. Thus, a better understanding of the requirements for an effective and safe antitumor immune response following ICI therapy is needed. Studies of both tumoral and systemic changes in the immune system following ICI therapy have yielded insight into the basis for both efficacy and resistance. Ultimately, by building on these insights, researchers should be able to combine ICIs with other agents, or design new immunotherapies, to achieve broader and more durable efficacy as well as greater safety. Here, we review the history and clinical utility of ICIs, the mechanisms of resistance to therapy, and local and systemic immune cell changes associated with outcome.
免疫检查点抑制剂（ICIs）在癌症免疫治疗领域留下了不可磨灭的印记。自 2011 年批准抗细胞毒性 T 淋巴细胞相关蛋白 4（抗 CTLA-4）用于晚期黑色素瘤以来，ICIs-现在还包括针对程序性细胞死亡 1（PD-1）及其配体（PD-L1）的抗体-迅速获得美国食品和药物管理局（FDA）批准，用于治疗多种癌症类型，患者的生存时间得到了前所未有的延长。然而，尽管 ICI 取得了成功，但这些药物的耐药性限制了能够实现持久反应的患者数量，免疫相关不良事件使治疗复杂化。因此，需要更好地了解 ICI 治疗后有效和安全的抗肿瘤免疫反应的要求。对 ICI 治疗后免疫系统中肿瘤和全身变化的研究深入了解了疗效和耐药性的基础。最终，通过利用这些见解，研究人员应该能够将 ICI 与其他药物联合使用，或设计新的免疫疗法，以实现更广泛、更持久的疗效和更高的安全性。在这里，我们回顾了 ICI 的历史和临床应用、治疗耐药的机制以及与疗效相关的局部和全身免疫细胞变化。
