PKCαinhibitors promote breast cancer immune evasion by maintaining PD-L1 stability  

作　　者：Jiaojiao Yu Yujin Xiang Yuzhen Gao Shan Chang Ren Kong Xiaoxi Lv Jinmei Yu Yunjie Jin Chenxi Li Yiran Ma Zhenhe Wang Jichao Zhou Hongyu Yuan Shuang Shang Fang Hua Xiaowei Zhang Bing Cui Pingping Li 

机构地区：[1]State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China [2]CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China [3]Institute of Bioinformatics and Medical Engineering,School of Electrical and Information Engineering,Jiangsu University of Technology,Changzhou 213001,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第10期4378-4395,共18页药学学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(82173853,82173379,82373914,82073892);Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2022-I2M-2-002,2021-I2M-1e026 and 2021-I2M-1e016,China);CAMS Central Public-interest Scientific Institution Basal Research Fund(2018PT35004,China);Beijing Outstanding Young Scientist Program(BJJWZYJH01201910023028,China);Peking Union Medical College Graduate Innovation Fund(2019-1007-05,China).

摘　　要：Protein kinase Cα(PKCα)regulates diverse biological functions of cancer cells and is a promising therapeutic target.However,clinical trials of PKC-targeted therapies have not yielded satisfactory results.Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms.In this study,we found that PKCαinhibition enhances CD8+T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice.We further identified PKCαas a critical regulator of programmed cell death-ligand 1(PD-L1)and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression.We demonstrated that PKCα-mediated PD-L1 phosphorylation promotes PD-L1 degradation throughβtransducin repeat-containing protein.Notably,the efficacy of PKCαinhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo.Clinical analysis revealed that PKCαexpression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer.This study demonstrated the antitumor capability of PKCα,identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies,and provided a proof of concept for targeting PKCαin combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer,especially TNBC.

关 键 词：Protein kinase C PD-L1 β-TRCP Degradation Immune evasion IMMUNOTHERAPY Combination strategies Breast cancer 

分 类 号：R96[医药卫生—药理学]