Abstract 4832: Differential roles of histone lactylation in regulating CD8 T cell effector functions and exhaustion

Abstract CD8 T cells undergo metabolic reprogramming upon activation to meet the increased energy demands associated with their cytotoxic functions. A hallmark of CD8 T cell activation is the upregulation of glycolysis, accompanied by increased lactate production. Lactylation, a post-translational modification of histones, derived from lactate, has garnered attention, though its specific role in CD8 T cell biology remains unclear. We have recently demonstrated the enrichment of histone lactylation marks, specifically H3K18-lactylation (H3K18la) and H3K9-lactylation (H3K9la), in human and murine CD8 T cells. Integrating ChIP-sequencing and RNA-sequencing data, we delineated the role of histone lactylation as transcriptional regulators of key genes essential for CD8 T cell-mediated cytotoxicity and effector functions. Importantly, our results, obtained from both in vitro experiments and in vivo disease models demonstrated that H3K18la and H3K9la exert differential effects across various CD8 T cell populations intricately tied to the metabolic profiles of distinct CD8 T cell subsets. Effector CD8 T cells, characterized by elevated glycolytic activity, exhibited correspondingly high levels of histone lactylation. In contrast, terminally exhausted CD8 T cells, where both glycolysis and mitochondrial metabolic pathways are impaired, displayed a marked reduction in histone lactylation. These cells were instead predominantly regulated by histone acetylation. Notably, co-immunoprecipitation assays revealed distinct epigenetic readers that specifically recognized histone lactylation marks, differentiating them from those binding to histone methylation or acetylation modifications. Modulating histone lactylation marks through metabolic and epigenetic interventions significantly altered CD8 T cell effector functions, including anti-tumor responses in preclinical models. Cumulatively, our findings demonstrated that histone lactylation, driven by intrinsic metabolic processes, regulates key aspects of CD8 T cell metabolism and function. Further, we identified distinct epigenetic mechanisms by which selective targeting of H3K18la and/or H3K9la can be leveraged to modulate CD8 T cell phenotype and functionality. Citation Format: Deblina Raychaudhuri, Pratishtha Singh, Bidisha Chakraborty, Aminah Tannir, Swadhin Meher, Sangeeta Goswami. Differential roles of histone lactylation in regulating CD8 T cell effector functions and exhaustion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4832.