Despite the clinical success of immune checkpoint blockade (ICB), in certain cancer types, most patients with cancer do not respond well. Furthermore, in patients for whom ICB is initially successful, this is often short-lived because of the development of resistance to ICB. The mechanisms underlying primary or secondary ICB resistance are incompletely understood. Here, we identified preferential activation and enhanced suppressive capacity of regulatory T cells (T reg cells) in αPD-L1 therapy–resistant solid tumor–bearing mice. T reg cell depletion reversed resistance to αPD-L1 with concomitant expansion of effector T cells. Moreover, we found that tumor-infiltrating T reg cells in human patients with skin cancer, and in patients with non–small cell lung cancer, up-regulated a suppressive transcriptional gene program after ICB treatment, which correlated with lack of treatment response. αPD-1/PD-L1–induced PD-1 + T reg cell activation was also seen in peripheral blood of patients with lung cancer and mesothelioma, especially in nonresponders. Together, these data reveal that treatment with αPD-1 and αPD-L1 unleashes the immunosuppressive role of T reg cells, resulting in therapy resistance, suggesting that T reg cell targeting is an important adjunct strategy to enhance therapeutic efficacy.

中文翻译：

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PD-L1 检查点阻断促进调节性 T 细胞活性，这是治疗耐药性的基础

尽管免疫检查点阻断 (ICB) 在临床上取得了成功，但在某些癌症类型中，大多数癌症患者反应不佳。此外，在 ICB 最初成功的患者中，由于对 ICB 产生耐药性，这通常是短暂的。初级或次级 ICB 耐药性的潜在机制尚不完全清楚。在这里，我们确定了调节性 T 细胞 (T注册细胞）在抗 αPD-L1 治疗的实体瘤荷瘤小鼠中。吨注册细胞耗竭逆转了对 αPD-L1 的抗性，同时伴随着效应 T 细胞的扩增。此外，我们发现肿瘤浸润性 T注册人类皮肤癌患者和非小细胞肺癌患者的细胞在 ICB 治疗后上调抑制性转录基因程序，这与缺乏治疗反应相关。αPD-1/PD-L1 诱导的 PD-1+吨注册在肺癌和间皮瘤患者的外周血中也观察到细胞活化，尤其是在无反应者中。总之，这些数据表明用 αPD-1 和 αPD-L1 治疗可释放 T 细胞的免疫抑制作用注册细胞，导致治疗耐药，表明 T注册细胞靶向是提高治疗效果的重要辅助策略。