Genetic deletion of the lysine methyltransferase significantly enhances the antitumor efficacy of CAR-T cells in xenograft models.
KMT5A acts as a negative regulator of CD8+ T cell function, as identified through CRISPR screening.
Deleting KMT5A in human CD8+ T cells improves effector functions and cytokine secretion.
Increased expression and chromatin accessibility of effector-related genes are observed following KMT5A deletion.
KMT5A-mediated modifications suppress CD8+ T cell functions by inhibiting the transcription factor SP1.
Pharmacological inhibition of KMT5A with UNC0379 enhances activation and cytotoxicity in human CD8+ T cells.
Simplified
BACKGROUND: Adoptive T-cell therapy has emerged as a promising therapeutic strategy for cancer treatment. However, clinical challenges persist, including the limited ability of CD8+T cells to infiltrate solid tumors and efficiently eliminate tumor cells. Given the critical role of epigenetic mechanisms in antitumor immunity, targeting epigenetic regulators represents a critical step toward optimizing adoptive T-cell therapies for solid tumors.
METHODS: To investigate the role ofin CD8+T cell function, we employed CRISPR screening to identifyas a negative regulator. We then genetically deletedin human CD8+T cells and systematically evaluated its impact on the antitumor efficacy of chimeric antigen receptor (CAR)-T cells using xenograft models. Furthermore, we used the small-molecule inhibitor UNC0379 to pharmacologically inhibit , meticulously assessing the consequent effects on CAR-T cell activation, cytotoxicity, and antitumor activity. KMT5A KMT5A KMT5A
RESULTS: We report that lysine methyltransferaseacts as a negative regulator of CD8+T cell function, identified via CRISPR screening.deletion in human CD8+T cells significantly enhances the antitumor efficacy of CAR CD8+T cells in xenograft models. In vitro immunophenotyping reveals thatdeletion improves effector functions, cytokine secretion, and early activation of CD8+T cells. Mechanistically,depletion increases the expression and chromatin accessibility of multiple effector-related genes in CD8+T cells. KMT5A-mediated histone H4 modifications and chromatin remodeling suppress CD8+T cell effector functions, partially via inhibition of the transcription factor. Notably, pharmacological inhibition of KMT5A using the small-molecule inhibitor UNC0379 enhanced activation, cytotoxicity, and antitumor activity in human CD8+T cells-a novel finding in this study. KMT5A KMT5A KMT5A KMT5A SP1
CONCLUSIONS: Our findings establishas an epigenetic regulator that impairs CD8+T cell function. These findings demonstrate that genetic or pharmacological (eg, UNC0379) targeting ofin CD8+T cells represents a viable therapeutic strategy to augment effector functions and improve adoptive T-cell therapies, particularly CAR-T cells, for solid tumors. KMT5A KMT5A
Key numbers
55%
Tumor Volume Reduction
Reduction in tumor volume in mice treated with -knockout CAR-T cells.
3×
Increased Cytotoxicity
Cytotoxicity of -knockout T cells compared to control T cells.
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