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UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity
Chuan He1, Xixin Xing1, Hsin-Yi Chen2
1Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
Abstract:
UFMylation is an emerging ubiquitin-like post-translational modification that regulates various biological processes. Dysregulation of the UFMylation pathway leads to human diseases, including cancers. However, the physiological role of UFMylation in T cells remains unclear. Here, we report that mice with conditional knockout (cKO) Ufl1, a UFMylation E3 ligase, in T cells exhibit effective tumor control. Single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in Ufl1 cKO mice. Mechanistically, UFL1 promotes PD-1 UFMylation to antagonize PD-1 ubiquitination and degradation. Furthermore, AMPK phosphorylates UFL1 at Thr536, disrupting PD-1 UFMylation to trigger its degradation. Of note, UFL1 ablation in T cells reduces PD-1 UFMylation, subsequently destabilizing PD-1 and enhancing CD8+ T cell activation. Thus, Ufl1 cKO mice bearing tumors have a better response to anti-CTLA-4 immunotherapy. Collectively, our findings uncover a crucial role of UFMylation in T cells and highlight UFL1 as a potential target for cancer treatment.
Insights
Targeting UFMylation E3 ligase UFL1 in T cells enhances anti-tumor immunity. Conditional knockout of UFL1 increases cytotoxic CD8+ T cells and improves immunotherapy response in mice.
Area of Science:
- Biochemistry and Molecular Biology
- Immunology
- Cancer Biology
Background:
- UFMylation is a ubiquitin-like modification regulating biological processes, with dysregulation linked to cancers.
- The role of UFMylation in T cells and its impact on anti-tumor immunity are not well understood.
Purpose of the Study:
- To investigate the physiological role of UFMylation in T cells.
- To determine the impact of UFMylation E3 ligase UFL1 on anti-tumor immunity and immunotherapy response.
Main Methods:
- Conditional knockout (cKO) of Ufl1 in T cells of mice.
- Single-cell RNA sequencing of tumor-infiltrating lymphocytes.
- Analysis of PD-1 ubiquitination and degradation.
- Immunotherapy with anti-CTLA-4.
Main Results:
- Ufl1 cKO in T cells led to effective tumor control and increased tumor-infiltrating cytotoxic CD8+ T cells.
- UFL1 promotes PD-1 UFMylation, inhibiting its ubiquitination and degradation.
- AMPK-mediated phosphorylation of UFL1 disrupts PD-1 UFMylation, leading to PD-1 degradation and enhanced T cell activation.
- Ufl1 ablation in T cells improved response to anti-CTLA-4 immunotherapy.
Conclusions:
- UFMylation plays a critical role in regulating T cell function and anti-tumor immunity.
- UFL1 is a key regulator of PD-1 stability in T cells.
- Targeting UFL1 represents a potential therapeutic strategy for enhancing cancer immunotherapy.
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