Demethylzeylasteral induces PD-L1 ubiquitin-proteasome degradation and promotes antitumor immunity via targeting USP22  

作　　者：Yanyan Zhang Yun Huang Dianping Yu Mengting Xu Hongmei Hu Qing Zhang Minchen Cai Xiangxin Geng Hongwei Zhang Jianhua Xia Mengmeng Guo Dong Lu Hanchi Xu Linyang Li Xing Zhang Qun Wang Sanhong Liu Weidong Zhang 

机构地区：[1]Shanghai Frontiers Science Center of TCM Chemical Biology,Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China [2]Department of Phytochemistry,School of Pharmacy,Second Military Medical University,Shanghai 200433,China [3]Institute of Medicinal Plant Development,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100193,China [4]The Research Center for Traditional Chinese Medicine,Shanghai Institute of Infectious Diseases and Biosafety,Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第10期4312-4328,共17页药学学报（英文版）

基　　金：funded by the National Key Research and Development Program of China(2022YFC3502000);National Natural Science Foundation of China(Nos.82141203,82374086,and 82104459);Shanghai Municipal Science and Technology Major Project(ZD2021CY001,China);Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTDD-202004,China);Science and Technology Commission of Shanghai Municipality(20YF1458700,China);Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(2023YZZ02,China)。

摘　　要：Programmed cell death ligand-1(PD-L1)is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1(PD-1)to promote immune escape of tumor cells.Compared with antibody therapies,small molecule drugs show better prospects due to their advantages such as higher bioavailability,better tissue penetration,and reduced risk of immunogenicity.Here,we found that the small molecule demethylzeylasteral(Dem)can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor cells.Mechanistically,Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation,resulting in increased ubiquitination and degradation of PD-L1 through the proteasome pathway.In addition,Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells(MDSCs)and regulatory T cells(Tregs)in tumor-infiltrating lymphocytes(TILs),thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 mice.Moreover,we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor therapy.Our study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.

关 键 词：DEMETHYLZEYLASTERAL PD-L1 USP22 DEUBIQUITINATION Tumor-infiltrating lymphocytes Colorectal cancer Immune checkpoint blockade Antitumor immunity 

分 类 号：R730.51[医药卫生—肿瘤]