HDAC inhibitors directly modulate T cell gene expression and signaling and promote development of effector-exhausted T cells in murine tumors [scRNA-seq]
Epigenetic regulation plays a crucial role in the development and progression of cancer, including the regulation of antitumor immunity. The reversible nature of epigenetic modifications offers potential therapeutic avenues for cancer treatment. In particular, Histone deacetylase (HDAC) inhibitors (HDACi) have been shown to promote antitumor T cell immunity by regulating myeloid cell types, enhancing tumor antigen presentation, and increasing expression of chemokines. HDACi are currently being evaluated to determine whether they can increase the response rate of immune checkpoint inhibitors (ICIs) in cancer patients. While the potential direct effect of HDACi on T cells likely impacts antitumor immunity, little is known about how HDAC inhibition alters the transcriptomic profile of T cells. Here, we show that two clinical-stage HDACi profoundly impact gene expression and signaling networks in CD8+ and CD4+ T cells. Specifically, HDACi promoted T cell effector function by enhancing expression of TNFa and IFNg and increasing CD8+ T cell cytotoxicity. Consistently, in a murine tumor model, HDACi led to enrichment of CD8+ T cell subsets with high expression of effector molecules (Prf1, Ifng, Gzmk, Grmb) but also molecules associated with T cell exhaustion (Tox, Pdcd1, Lag3, Havcr2). HDACi further generated a TME dominated by myeloid cells with immune suppressive signatures. These results indicate that HDACi directly and favorably augment T cell effector function but also increase their exhaustion signal in the TME, which may add a layer of complexity for achieving clinical benefit in combination with ICIs. Overall design: The goal of this study is to assess effect of HDACi and ICI alone and in combination on tumor microenvironment in KP mouse model using single-cell RNAseq