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The E3 ubiquitin ligase TRAF6 controls CTLA-4 turnover and promotes T-cell-mediated antitumor immunity

Cellular & Molecular Immunology volume 21, pages 97–99 (2024)Cite this article

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Yu et al. [1] reported that the tumor necrosis factor (TNF) receptor OX40 (CD134)-TNF receptor-associated factor 6 (TRAF6) axis mediates Lys63-linked ubiquitination and subsequent lysosomal degradation of cytotoxic T-lymphocyte antigen 4 (CTLA-4), leading to the enhancement of CD8+ T-cell-mediated antitumor immunity. Their findings unveil a previously unknown mechanism in controlling the stability of the immune checkpoint CTLA-4 and provide a potential therapeutic target for the improvement of T-cell-based immunotherapy.

CTLA-4 is an inhibitory receptor belonging to the CD28 immunoglobulin subfamily. It is a well-known protein receptor that inhibits the antitumor immune activity of T cells. Monoclonal antibodies (mAbs) against CTLA-4, ipilimumab and tremelimumab have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of melanoma [2]. Both antibodies produced objective clinical responses in a proportion of patients with melanoma, and 18% of the ipilimumab-treated patients survived beyond two years [2]. However, CTLA-4 inhibitors still have limitations in the clinical application for cancer treatment, mainly due to their high rates of immunotherapy-related adverse effects, such as pneumonitis, gastritis, hepatitis, and nephritis, and the low response rate in patients.

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Acknowledgements

Work in the Zhou Lab is funded by the Key Project of the National Natural Science Foundation of China (81830093), the Non-Profit Central Research Institute Fund of CAMS (2022-RC310-05, 2021-RC310-003, 2020-RC310-002), CAMS Initiative for Innovative Medicine (2022-I2M-2-001), and the National Natural Science Foundation of China (82372944).

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  1. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China

    Xiao-Liang Jie, Hua Guo & Guang-Biao Zhou

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  1. Xiao-Liang Jie
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Correspondence to Guang-Biao Zhou.

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Jie, XL., Guo, H. & Zhou, GB. The E3 ubiquitin ligase TRAF6 controls CTLA-4 turnover and promotes T-cell-mediated antitumor immunity. Cell Mol Immunol 21, 97–99 (2024). https://doi.org/10.1038/s41423-023-01105-x

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