CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy
CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy
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DOI：
10.1172/jci.insight.97828
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发表时间：
2018-04-19
期刊：
影响因子：
8
通讯作者：
Dong, Haidong
中科院分区：
文献类型：
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作者：
Yan, Yiyi;Cao, Siyu;Dong, Haidong
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，但发现一些对初始抗PD-1治疗无反应的患者可从添加补救化疗中获益。然而，负责成功的化学免疫疗法的机制并不完全清楚。在这里，我们表明，表达趋化因子受体CX 3CR 1的循环CD 8（+）T细胞亚群能够承受化疗的毒性，并且在对化学免疫治疗（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CX 3CR 1（+）CD 8（+）T细胞具有效应记忆表型和通过ABCB 1转运蛋白外排化疗药物的能力。与临床观察一致，我们的临床前模型确定了导致CX 3CR 1（+）CD 8（+）T细胞增加的化学免疫治疗的最佳顺序。综上所述，我们发现了一个PD-1治疗反应性CD 8（+）T细胞亚群，它们能够耐受化疗并执行肿瘤排斥反应，具有独特的药物外排（ABCB 1）、细胞溶解活性（颗粒酶B和穿孔素）以及迁移和保留（CX 3 CR 1和CD 11 a）肿瘤部位的能力。未来监测和增加CX 3CR 1（+）CD 8（+）T细胞频率的策略可能有助于设计有效的化学免疫疗法，以克服癌症对免疫检查点阻断疗法的耐药性。
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.