The OX40-TRAF6 axis promotes CTLA-4 degradation to augment antitumor CD8^(+)T-cell immunity  

作　　者：Jizhang Yu Jikai Cui Xi Zhang Heng Xu Zhang Chen Yuan Li Yuqing Niu Song Wang Shuan Ran Yanqiang Zou Weicong Ye Dan Zhang Cheng Zhou Jiahong Xia Jie Wu 

机构地区：[1]Department of Cardiovascular Surgery,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China [2]Key Laboratory of Organ Transplantation,Ministry of Education,NHC Key Laboratory of Organ Transplantation,Key Laboratory of Organ Transplantation,Chinese Academy of Medical Sciences,Wuhan,China [3]Center for Translational Medicine,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China [4]Institute of Translational Medicine,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China [5]Cancer Center,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China

出　　处：《Cellular & Molecular Immunology》2023年第12期1445-1456,共12页中国免疫学杂志（英文版）

基　　金：supported by the National Natural Science Foundation of China(82071803,82241217,and 82271811);Fundamental Research Funds for the Central Universities(2021GCRC037);Project Funded by China Postdoctoral Science Foundation(2021M691155).

摘　　要：Immune checkpoint blockade(ICB),including anti-cytotoxic T-lymphocyte associated protein 4(CTLA-4),benefits only a limited number of patients with cancer.Understanding the in-depth regulatory mechanism of CTLA-4 protein stability and its functional significance may help identify ICB resistance mechanisms and assist in the development of novel immunotherapeutic modalities to improve ICB efficacy.Here,we identified that TNF receptor-associated factor 6(TRAF6)mediates Lys63-linked ubiquitination and subsequent lysosomal degradation of CTLA-4.Moreover,by using TRAF6-deficient mice and retroviral overexpression experiments,we demonstrated that TRAF6 promotes CTLA-4 degradation in a T-cell-intrinsic manner,which is dependent on the RING domain of TRAF6.This intrinsic regulatory mechanism contributes to CD8+T-cell-mediated antitumor immunity in vivo.Additionally,by using an OX40 agonist,we demonstrated that the OX40-TRAF6 axis is responsible for CTLA-4 degradation,thereby controlling antitumor immunity in both tumor-bearing mice and patients with cancer.Overall,our findings demonstrate that the OX40-TRAF6 axis promotes CTLA-4 degradation and is a potential therapeutic target for the improvement of T-cell-based immunotherapies.

关 键 词：Antitumor immunity CD8^(+)T cell T-cell-based immunotherapy TRAF6 CTLA-4 

分 类 号：R73[医药卫生—肿瘤] R392[医药卫生—临床医学]