Abstract A066: Histone deacetylase 11 is an epigenetic regulator of T-cell pro-inflammatory function and novel target for enhancing T-cell anti-tumor activity

Abstract

Abstract The efficacy of immunotherapy is dependent on the ability of antigen-specific T-cells to mount a proper anti-tumor response while avoiding a plethora of immunosuppressive mechanisms. Unfortunately, these immunosuppressive mechanisms often overwhelm the T-cell response, resulting in patients failing to respond. Histone deacetylases (HDACs) are a family of epigenetic modifiers named for their ability to remove acetyl groups from lysine residues of histone tails, thereby regulating the chromatin structure and gene expression. Here we report that HDAC11, the most recently discovered HDAC, is a regulator of T-cell pro-inflammatory function. Previous reports have shown HDAC11 expression to be tissue restricted. Consequently, we compared expression levels of HDAC11 using an eGFP reporter mouse, in various immune cells. It was found that T-cells expressed relatively high levels of HDAC11. However, while resting T-cells, both central memory and naïve, had high levels of HDAC11 expression, effector or effector memory T-cells displayed lower levels. Additionally, T-cells experienced rapid down-regulation of HDAC11 upon activation. To expand upon these observations, the function of T-cells from HDAC11KO mice were investigated. Initial experiments revealed no gross changes in the numbers or maturation of T-cells. However, HDAC11KO mice displayed an increased percentage of central memory CD8+ T-cells (p<0.05). Additionally, upon activation these T-cells were more apt to acquire effector status (p<0.001). Upon activation, HDAC11KO T-cells demonstrated a robust increase in IL-2, TNF and IFNγ production (p<0.01), but showed no differences in Th2 or Th17 cytokine production. These T-cells also expressed higher levels of the effector molecules granzyme B and perforin (p<0.01). Moreover, post-activation, CD8+ T-cells lacking HDAC11 also displayed a higher percentage of proliferating cells, and more divisions of proliferating cells (p<0.01). HDAC11KO T-cells displayed higher resistance to proliferative suppression by Tregs and failed to succumb to anergy in a high dose antigen model. Indeed, while OTII T-cells from mice injected with high dose OVA peptide displayed reduced levels of IFNγ production compared to cells from non-injected mice after rechallenge, HDAC11KO/OTII T-cells had an increase in IFNγ production. Mechanistically, T-cells devoid of HDAC11 did not appear to have differences in TCR signaling, but did express higher levels of the transcription factors EOMES and T-bet. Chromatin immunoprecipitation (ChIP) revealed higher basal levels of acetylation of these genes in HDAC11KO mice. ChIP analysis also revealed interactions of HDAC11 at the promoters of both EOMES and T-bet. In a graft vs. host disease (GvHD) model, HDAC11KO T-cells produced a more rapid onset of GvHD, and were able to do so with transfers of cell numbers below that able to induce GvHD using WT T-cells (p<0.01). This GvHD was characterized by greater levels of IFNγ and TNF as well as increased T-cell expansion (p<0.05). In a B16 melanoma model, adoptive transfer of HDAC11KO T-cells resulted in delayed tumor progression (p<0.05) compared to WT T-cells. To begin investigating the clinical potential of these data, the expression levels of HDAC11 were investigated in melanoma tumor sections utilized to grow tumor infiltrating lymphocytes (TIL) for clinical trials of adoptive cell therapy. A reduced level of HDAC11 was found in tumor sections from those patients responding to TIL therapy compared to progressing patients (p<0.01). Collectively, beyond demonstrating HDAC11 as a novel epigenetic regulator of T-cell pro-inflammatory function, these results highlight HDAC11 as a novel target for enhancing the efficacy of immunotherapy. Citation Format: David M. Woods, Andressa L. Sodre, Karrune Woan, Alejandro Villagra, Amod Sarnaik, Jeffrey Weber, Eduardo M. Sotomayor. Histone deacetylase 11 is an epigenetic regulator of T-cell pro-inflammatory function and novel target for enhancing T-cell anti-tumor activity. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A066.