武汉大学李姝等研究人员合作发现，PD-1信号通过MARCH5介导的泛素化和降解负向调节常见细胞因子受体γ链来抑制抗肿瘤免疫力。这一研究成果于2023年11月6日在线发表在国际学术期刊《细胞研究》上。

研究人员发现PD-1结合会导致BATF依赖性转录诱导膜相关E3泛素连接酶MARCH5，后者介导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还能激活SHP2，使γc^Y357去磷酸化，从而导致γc家族细胞因子触发的信号转导受损。相反，PD-1阻断可恢复γc的水平和活性，从而使CD8⁺ T细胞对IL-2敏感。

研究人员还发现了匹伐他汀钙可作为MARCH5的抑制剂，它与PD-1阻断和IL-2结合可显著提高小鼠抗肿瘤免疫疗法的疗效。这些研究结果揭示了PD-1信号拮抗γc家族细胞因子触发的免疫激活的机制，并证明可以利用其潜在机制提高癌症联合免疫疗法的疗效。

据介绍，与单一疗法相比，PD-1阻断剂和IL-2的联合疗法可大幅提高抗肿瘤疗效。联合疗法产生协同效应的内在机制仍是一个谜。

附：英文原文

Title: PD-1 signaling negatively regulates the common cytokine receptor γ chain via MARCH5-mediated ubiquitination and degradation to suppress anti-tumor immunity

Author: Liu, Rui, Zeng, Lin-Wen, Li, Hui-Fang, Shi, Jun-Ge, Zhong, Bo, Shu, Hong-Bing, Li, Shu

Issue&Volume: 2023-11-06

Abstract: 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.

DOI: 10.1038/s41422-023-00890-4

Source: https://www.nature.com/articles/s41422-023-00890-4