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

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外文摘要：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.

外文关键词：

Antitumor immunityCD8+T cellT-cell-based immunotherapyTRAF6CTLA-4

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

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作者单位：

Department of Cardiovascular Surgery,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China

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

Center for Translational Medicine,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China

Institute of Translational Medicine,Tongji Medical Coll

Cancer Center,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China

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基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaFundamental Research Funds for the Central UniversitiesProject Funded by China Postdoctoral Science Foundation

项目编号：

8207180382241217822718112021GCRC0372021M691155

出版年：

2023

DOI：

10.1038/s41423-023-01093-y

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(12)

参考文献量63