与单一疗法相比，PD-1阻断剂和IL-2的联合疗法显着提高了抗肿瘤疗效。联合疗法产生协同效应的潜在机制仍然是个谜。在这里，我们表明，PD-1 连接导致膜相关 E3 泛素连接酶 MARCH5 的 BATF 依赖性转录诱导，介导 K27 连接的多泛素化和常见细胞因子受体 γ 链 (γc) 的溶酶体降解。 PD-1 连接还会激活 SHP2，后者使 γcY357 去磷酸化，导致 γc 家族细胞因子触发的信号传导受损。相反，PD-1 阻断可恢复 γc 水平和活性，从而使 CD8 T 细胞对 IL-2 敏感。我们还鉴定了匹伐他汀钙作为 MARCH5 的抑制剂，与 PD-1 阻断和 IL-2 联合显着提高小鼠抗肿瘤免疫治疗的疗效。我们的研究结果揭示了 PD-1 信号传导拮抗 γc 家族细胞因子触发的免疫激活的机制，并证明可以利用潜在机制来提高癌症联合免疫疗法的疗效。© 2023。作者。

Combination therapy with PD-1 blockade and IL-2 substantially improves anti-tumor efficacy comparing to monotherapy. The underlying mechanisms responsible for the synergistic effects of the combination therapy remain enigmatic. Here we show that PD-1 ligation results in BATF-dependent transcriptional induction of the membrane-associated E3 ubiquitin ligase MARCH5, which mediates K27-linked polyubiquitination and lysosomal degradation of the common cytokine receptor γ chain (γc). PD-1 ligation also activates SHP2, which dephosphorylates γcY357, leading to impairment of γc family cytokine-triggered signaling. Conversely, PD-1 blockade restores γc level and activity, thereby sensitizing CD8+ T cells to IL-2. We also identified Pitavastatin Calcium as an inhibitor of MARCH5, which combined with PD-1 blockade and IL-2 significantly improves the efficacy of anti-tumor immunotherapy in mice. Our findings uncover the mechanisms by which PD-1 signaling antagonizes γc family cytokine-triggered immune activation and demonstrate that the underlying mechanisms can be exploited for increased efficacy of combination immunotherapy of cancer.© 2023. The Author(s).