Manipulating the epigenetic framework of T cells with histone deacetylase inhibitors for more robust and durable anti-tumor responses

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Abstract Malignant cells often harbor an imbalance in histone acetyltransferase and histone deacetylase (HDAC) activity, which can be disrupted by HDAC inhibitors. We hypothesized that HDAC inhibition can boost anti-tumor T cell responses by modifying tumor cell phenotypes as well as directly altering the transcriptional framework of tumor-specific T cells. To test this, we treated two murine breast cancer cell lines, TS/A and 4T1, with class I (entinostat), or pan-specific (panobinostat), HDAC inhibitors. Culture of tumor cells with either inhibitor increased surface expression of MHC and costimulatory molecules as well as T cell chemoattractants. Tumor growth was significantly impaired by HDAC inhibition in a manner absolutely dependent on adaptive immunity, specifically CD8 T cells and IFNγ production, but not CD4 T cells or B cells. Indeed, CD8 T cell production of effector cytokines was dramatically augmented. This enhanced effector function was paralleled by an increase in T-bet and a decrease in Eomes, consistent with a transcriptional program that is less susceptible to exhaustion. We also found that simply adjusting timing of HDAC inhibition relative to T cell activation could abolish anti-tumor effects or lead to rejection in nearly 50% of mice. These findings corresponded with a significant shift in the responding T cell repertoire. Collectively, our data suggests that HDAC inhibition reprograms the transcriptional profile of T cells in ways that impact priming, improve effector functions, and reduce susceptibility to exhaustion. Thus, appropriately timed HDAC inhibition may synergistically potentiate existing tumor immunotherapies, like T cell reinvigoration strategies.