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

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

机构地区：[1]Department of Infectious Diseases,Zhongnan Hospital of Wuhan University,Frontier Science Center for Immunology and Metabolism,Medical Research Institute,Research Unit of Innate Immune and Inflammatory Diseases(2019RU063),Chinese Academy of Medical Sciences,Wuhan University,Wuhan,Hubei,China

出　　处：《Cell Research》2023年第12期923-939,共17页细胞研究（英文版）

基　　金：supported by grants from the State Key R&D Program of China(2022YFA1304900);the National Natural Science Foundation of China(32188101,31830024,32070775 and 32300758);the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071);the Major Scientific and Technological Project of Hubei Province(2022ACA005);the Fundamental Research Funds for the Central Universities(2042022dx0003);the China Postdoctoral Science Foundation(2022TQ0236,2023M732694).

摘　　要：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 receptorγchain(γ_(c)).PD-1 ligation also activates SHP2,which dephosphorylates γc^(Y357),leading to impairment of γ_(c) family cytokine-triggered signaling.Conversely,PD-1 blockade restores γ_(c) 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 antitumor immunotherapy in mice.Our findings uncover the mechanisms by which PD-1 signaling antagonizesγc family cytokinetriggered immune activation and demonstrate that the underlying mechanisms can be exploited for increased efficacy of combination immunotherapy of cancer.

关 键 词：CYTOKINE UBIQUITIN MARCH 

分 类 号：R730.5[医药卫生—肿瘤]