Division of Medical Oncology.
Department of Urology.
JCI Insight. 2018 Apr 19;3(8). doi: 10.1172/jci.insight.97828.
Although immune checkpoint inhibitors have resulted in durable clinical benefits in a subset of patients with advanced cancer, some patients who did not respond to initial anti-PD-1 therapy have been found to benefit from the addition of salvage chemotherapy. However, the mechanism responsible for the successful chemoimmunotherapy is not completely understood. Here we show that a subset of circulating CD8+ T cells expressing the chemokine receptor CX3CR1 are able to withstand the toxicity of chemotherapy and are increased in patients with metastatic melanoma who responded to chemoimmunotherapy (paclitaxel and carboplatin plus PD-1 blockade). These CX3CR1+CD8+ T cells have effector memory phenotypes and the ability to efflux chemotherapy drugs via the ABCB1 transporter. In line with clinical observation, our preclinical models identified an optimal sequencing of chemoimmunotherapy that resulted in an increase of CX3CR1+CD8+ T cells. Taken together, we found a subset of PD-1 therapy-responsive CD8+ T cells that were capable of withstanding chemotherapy and executing tumor rejection with their unique abilities of drug efflux (ABCB1), cytolytic activity (granzyme B and perforin), and migration to and retention (CX3CR1 and CD11a) at tumor sites. Future strategies to monitor and increase the frequency of CX3CR1+CD8+ T cells may help to design effective chemoimmunotherapy to overcome cancer resistance to immune checkpoint blockade therapy.
尽管免疫检查点抑制剂在一部分晚期癌症患者中产生了持久的临床获益，但一些对初始抗 PD-1 治疗无反应的患者被发现从挽救性化疗的加入中获益。然而，负责成功的化疗免疫治疗的机制尚不完全清楚。在这里，我们表明，表达趋化因子受体 CX3CR1 的循环 CD8+T 细胞的亚群能够耐受化疗的毒性，并在对化疗免疫治疗（紫杉醇和卡铂加 PD-1 阻断）有反应的转移性黑色素瘤患者中增加。这些 CX3CR1+CD8+T 细胞具有效应记忆表型，并且能够通过 ABCB1 转运体排出化疗药物。与临床观察一致，我们的临床前模型确定了化疗免疫治疗的最佳顺序，导致 CX3CR1+CD8+T 细胞增加。总之，我们发现了一部分 PD-1 治疗反应性 CD8+T 细胞，它们能够耐受化疗，并通过其独特的药物外排（ABCB1）、细胞溶解活性（颗粒酶 B 和穿孔素）和向肿瘤部位迁移和保留（CX3CR1 和 CD11a）的能力来执行肿瘤排斥。未来监测和增加 CX3CR1+CD8+T 细胞频率的策略可能有助于设计有效的化疗免疫治疗，以克服癌症对免疫检查点阻断治疗的耐药性。
