Targeting Histone Crotonylation to epigenetically reprogram exhausted T cells and enhance the efficacy of immunotherapy
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Date
2025-05
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The Ohio State University
Abstract
Exhaustion of CD8 T cells during cancer or chronic infections remains a significant barrier to T cell immunotherapies. Recent studies showed that distinct epigenetic changes drive exhaustion by silencing effector and memory-related genes, thereby establishing the dysfunctional state of exhausted T cells (TEX). Thus, targeting epigenetic regulation of exhaustion is crucial for restoring TEX cell function. Short chain fatty acids (SCFAs) are emerging as key mediators linking cellular metabolism to gene regulation, with growing evidence suggesting their importance in immune system modulation. Notably, certain SCFAs naturally produced by human microbiota have been demonstrated to modulate host immune responses through epigenetic mechanisms, making them promising candidates for therapeutic intervention. To investigate the effects of SCFAs on TEX cell epigenetic programming, we utilized innovative in vitro T cell exhaustion models that generate stable terminal dysfunction in both human and mouse CD8 T cells. By inducing a state of exhaustion that recapitulates key molecular and functional features observed in cancer and chronic infections, these models enabled us to assess how SCFA treatment affects T cell function and memory-associated stemness properties. We discovered that crotonate, a specific microbial SCFA, elicited a significant recovery of polyfunctionality and memory programs within both human and mouse dysfunctional T cells. Crotonate-treated TEX cells exhibited renewed effector capabilities, demonstrating enhanced cytokine production, degranulation, and tumor-killing activity characteristic of functional T cells. Additionally, we employed in vivo murine tumor models and chronic LCMV infection models to assess crotonate’s therapeutic potential. Melanoma-bearing mice treated with crotonate exhibited a marked reduction in tumor growth. Furthermore, during chronic LCMV infection, crotonate enhanced the progenitor-like state of TEX, promoting their persistence and function. These findings identify a novel microbial SCFA that functions as a metabolic-epigenetic regulator capable of reactivating effector programs in TEX cells while blocking terminal exhaustion. This provides insights for developing new therapeutic approaches to epigenetically reprogram TEX cells and enhance the efficacy of cancer immunotherapy.
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Travel Awardee: College of Medicine Trainee Research Day (April 2025)
The American Association of Immunologists (AAI) Abstract Acceptance for Poster Presentation (2025)
The American Association of Immunologists (AAI) Abstract Acceptance for Poster Presentation (2025)
Keywords
Epigenetics, Cancer Immunotherapy, T cell Exhaustion, Short chain fatty acids