Ribas Antoni, Wolchok Jedd D
Department of Medicine, Division of Hematology-Oncology; Department of Surgery, Division of Surgical Oncology; and Department of Molecular and Medical Pharmacology, Jonsson Comprehensive Cancer Center and Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Medicine, Ludwig Center and Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Science. 2018 Mar 23;359(6382):1350-1355. doi: 10.1126/science.aar4060. Epub 2018 Mar 22.
The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.
限制抗肿瘤反应的免疫激活负调节因子（免疫检查点）的释放，已在多种癌症患者中产生了前所未有的持久肿瘤反应率。这可以通过单独或联合使用阻断细胞毒性T淋巴细胞相关蛋白4（CTLA-4）或程序性细胞死亡1（PD-1）途径的抗体来实现。诱导免疫反应的主要前提是存在受特定免疫检查点限制的抗肿瘤T细胞。大多数有肿瘤反应的患者维持着持久的疾病控制，但三分之一的患者会复发。目前对获得性耐药机制了解甚少，但有证据表明其改变集中在抗原呈递和干扰素-γ信号通路。新一代联合疗法可能会克服免疫检查点疗法的耐药机制。
