Investigating the Role of HDAC8 in CD4 +T Cells

Abstract

Abstract T cell exclusion restricts immune checkpoint blockade (ICB) efficacy for some hepatocellular carcinoma (HCC) patients. Epigenetic therapy provides new opportunities to rewire transcriptional programs. We have recently elucidated that pharmacological inhibition of histone deacetylase 8 (HDAC8) resulted in increased CD8 +T cell infiltration and enhanced ICB therapy efficacy in HCC. Moreover, this combined immunotherapy induced durable survival benefits even after tumor rechallenge accompanied by elevated memory T cells (Sci Transl Med, 2021). In this study, we found that HDAC8 inhibition increased memory T cells in HCC tumor-bearing mice. Interestingly, HDAC8 knockdown in tumor cells did not influence the effect of pharmacological HDAC8 inhibition in T cell activation and cytotoxic function, suggesting an immune cell-intrinsic role of HDAC8. HDAC8 was highly expressed in T cells instead of other immune cells. Notably, HDAC8 inhibition upregulated memory-related gene expression in CD4 +T cells, but not in CD8 +T cells. Besides, HDAC8 inhibition increased acetylation of structural maintenance of chromosome 3 (SMC3ac), a ring-shaped cohesin component in topologically entrapping enhancers and promoters which may modulate gene expression. Moreover, inhibiting HDAC8 increased SMC3ac binding onto the targeting gene promoter region and induced mRNA expression in CD4-expressing Jurkat cells. These data suggest that HDAC8 inhibition exerts memory T cell formation through SMC3ac-mediated epigenome reprogramming in CD4 +T cells, thus providing insights into developing effective cancer immunotherapy. Acknowledgment: This work is supported by the RGC Collaborative Research Fund (C4045-18W), Li Ka Shing Foundation, TRS T11-706/18-N and EpiHK.