Epigenetic therapy provides new opportunities to rewire cancer‐associated transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune excluded phenotype, such as hepatocellular carcinoma (HCC), remain incompletely defined. We have previously elucidated pharmacological inhibition of histone deacetylase 8 (HDAC8) resulted in increased infiltration of CD8⁺ T cells through enhancer reprogramming and enhanced efficacy of immune‐checkpoint blockade (ICB) therapy in HCC‐bearing mice, which was accompanied with a remarkable elevation of memory T cells (Science Translational Medicine, 2021Apr7;13(588):eaaz6804). Here, we further investigated HDAC8-regulated tumor‐intrinsic and ‐extrinsic epigenetic programs in promoting immune evasion by suppressing T cell memory formation. We found that selective HDAC8 inhibition increases acetylation of structural maintenance of chromosomes protein 3 (SMC3) a cohesin subunit important for 3D genome organization in T cells in vitro, which is associated with significant up-regulation of CD28, a costimulatory molecule that promotes memory CD8⁺ T cell development. To test whether T cell‐intrinsic HDAC8 engages unique molecular pathways to restrict long‐lasting memory T cells, we propose to delineate HDAC8-controlled chromatin loop formation by performing Hi-C. Integrating with RNA-seq, indicated that selective HDAC8 inhibition restricted extended loop enlargement and controlled CD28 gene expression. Coupled with ChIP-seq and Hi-ChIP genome-wide analysis, we will further explore HDAC8/cohesion-mediated 3D genome re-organization in T cell memory formation in vitro. This study will identify new epigenetic pathways by which 3D genome organization drives T cell memory formation and may lead to novel therapeutic avenues of precision immunotherapy for HCC. 
 

HDAC8 memory T cell HCC 3D genome reorganization