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Destruction of VISTA by TRIM25 ablation in T cells potentiates cancer immunotherapy
Yishuang Sun1,2,3, Zijian Zhang4,5, Haiou Li6
1Department of Hepatobiliary and Pancreatic Surgery, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China.
Abstract:
The limited success of current immunotherapies emphasizes the need for new targets and combination treatments. V-domain Ig suppressor of T cell activation (VISTA) is a promising immune checkpoint target in cancer immunotherapy, but its regulatory mechanism is poorly understood. Through CRISPR knockout screening and proteomic analysis, we identify tripartite motif containing 25 (TRIM25) as a positive regulator for VISTA largely through antagonizing its degradation signaling. Moreover, ERK-mediated phosphorylation of VISTA at Thr284 enhances its interaction with TRIM25, leading to VISTA stabilization. A VISTA-derived phospho-peptide competitively disrupts TRIM25-VISTA interaction, thereby reducing VISTA expression and potentiating the anti-tumor efficacy of PD-1/PD-L1 blockade. Moreover, single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in mice with T cell-specific knockout of Trim25. Of note, genetic ablation of Trim25 in T cells not only improves anti-PD-L1 immunotherapy, but also significantly ameliorates CAR T anti-tumor activity in various mouse tumor models. Collectively, this study unveils a mechanism for VISTA regulation in T cells and highlights targeting TRIM25-VISTA as a potential strategy to enhance tumor immunotherapy.
Insights
Researchers discovered that TRIM25 stabilizes VISTA, a key target in cancer immunotherapy. Disrupting this interaction enhances anti-tumor immunity and improves responses to PD-1/PD-L1 blockade and CAR T cell therapy.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Current immunotherapies have limited efficacy, necessitating novel targets and combination strategies.
- V-domain Ig suppressor of T cell activation (VISTA) is a promising immune checkpoint target, but its regulation is unclear.
- Understanding VISTA's regulatory mechanisms is crucial for improving cancer immunotherapy.
Purpose of the Study:
- To identify regulators of VISTA and elucidate its mechanism of action.
- To explore the potential of targeting the VISTA regulatory pathway for enhanced anti-tumor immunity.
- To investigate the role of TRIM25 in VISTA stabilization and its impact on immunotherapy.
Main Methods:
- CRISPR knockout screening and proteomic analysis to identify VISTA regulators.
- ERK-mediated phosphorylation site mapping on VISTA.
- Development of a VISTA-derived phospho-peptide for therapeutic intervention.
- Single-cell RNA sequencing to analyze immune cell infiltration in Trim25 knockout models.
Main Results:
- Tripartite motif containing 25 (TRIM25) was identified as a positive regulator of VISTA by inhibiting its degradation.
- ERK-mediated phosphorylation of VISTA at Thr284 enhances its interaction with TRIM25, stabilizing VISTA.
- A VISTA-derived phospho-peptide disrupted the TRIM25-VISTA interaction, reducing VISTA expression and enhancing anti-PD-1/PD-L1 blockade efficacy.
- T cell-specific knockout of Trim25 increased tumor-infiltrating cytotoxic CD8+ T cells and improved anti-tumor activity in both anti-PD-L1 and CAR T cell therapy models.
Conclusions:
- TRIM25 stabilizes VISTA through a phosphorylation-dependent interaction, representing a novel regulatory mechanism.
- Targeting the TRIM25-VISTA interaction offers a potential strategy to enhance cancer immunotherapy efficacy.
- Modulating TRIM25 in T cells can potentiate anti-tumor responses, suggesting therapeutic potential for VISTA-targeted strategies.
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