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

Cellular & Molecular Immunology volume 20, pages 1445–1456 (2023)Cite this article

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Abstract

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.

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Data availability

The GEO accession number for the RNA-sequencing data is GSE222539. MS data (PRIDE: PXD039327) have been deposited into the PRIDE Archive. All data needed to evaluate the conclusions made in this paper are presented in the paper or in Supplementary Materials. Additional data are available from the authors upon request.

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Acknowledgements

The authors wish to thank Dr. Ding Ma (Huazhong University of Science and Technology) for providing the B16 and MC38 cells, Dr. Peng Zhang (Wuhan University) for the Traf6fl mice, Dr. Xiangliang Yang (Huazhong University of Science and Technology) for the B16-OVA cells, Dr. Xiaokun Shu (University of California) for the SPARK system, Dr. Long Yu and Dr. Ning Li for their technical guidance, and Dr. Xiaoyi Li for the operational support. Furthermore, the authors acknowledge the Medical Subcenter at the HUST Analytical & Testing Center and the Center of Experimental Animals of Tongji Medical College for providing outstanding services. This study was supported by the National Natural Science Foundation of China (82071803, 82241217, and 82271811), Fundamental Research Funds for the Central Universities (2021GCRC037), and Project Funded by China Postdoctoral Science Foundation (2021M691155).

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  1. These authors contributed equally: Jizhang Yu, Jikai Cui, Xi Zhang.

Authors and Affiliations

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

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

  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

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

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

    Jizhang Yu, Jikai Cui, Xi Zhang, Heng Xu, Zhang Chen, Yuan Li, Yuqing Niu, Song Wang, Shuan Ran, Yanqiang Zou, Weicong Ye, Dan Zhang, Jiahong Xia & Jie Wu

  4. Institute of Translational Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Jizhang Yu, Jiahong Xia & Jie Wu

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

    Dan Zhang

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Contributions

Designed the experiments: JX, JW, DZ; Performed the biological experiments: JY, JC, YL, YZ; Generated cell lines: YN. SW; Performed the bioinformatic analysis: WY, HX, ZC; Analyzed the biological data: SR, SW; Wrote the manuscript (original draft): JY, JC, CZ; Wrote the manuscript (review & editing): XZ, JW.

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Correspondence to Jiahong Xia or Jie Wu.

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Yu, J., Cui, J., Zhang, X. et al. The OX40-TRAF6 axis promotes CTLA-4 degradation to augment antitumor CD8+ T-cell immunity. Cell Mol Immunol 20, 1445–1456 (2023). https://doi.org/10.1038/s41423-023-01093-y

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