Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA.
Nat Rev Drug Discov. 2022 Jul;21(7):529-540. doi: 10.1038/s41573-022-00493-5. Epub 2022 Jun 14.
Tumours employ various tactics to adapt and eventually resist immune attack. These mechanisms are collectively called adaptive immune resistance (AIR). The first defined and therapeutically validated AIR mechanism is the selective induction of programmed cell death 1 ligand 1 (PDL1) by interferon-γ in the tumour. Blockade of PDL1 binding to its receptor PD1 by antibodies (anti-PD therapy) has resulted in remission of a fraction of patients with advanced-stage cancer, especially in solid tumours. However, many clinical trials combining anti-PD therapy with other antitumour drugs conducted without a strong mechanistic rationale have failed to identify a synergistic or additive effect. In this Perspective article, we discuss why defining AIR mechanisms at the tumour site should be a key focus to direct future drug development as well as practical approaches to improve current cancer therapy.
肿瘤采用各种策略来适应并最终抵抗免疫攻击。这些机制统称为适应性免疫抵抗（AIR）。第一个被定义并经治疗验证的 AIR 机制是干扰素-γ在肿瘤中选择性诱导程序性细胞死亡配体 1（PDL1）的表达。通过抗体阻断 PDL1 与其受体 PD1 的结合（抗 PD 治疗）已导致一部分晚期癌症患者（尤其是实体瘤患者）的缓解，但许多未基于明确机制学原理而将抗 PD 治疗与其他抗肿瘤药物联合使用的临床试验未能确定协同或相加效应。在本文观点部分，我们讨论了为何在肿瘤部位定义 AIR 机制应成为指导未来药物开发的重点，并探讨了改善当前癌症治疗的实用方法。
