Abstract 4700: Manipulating the breast tumor microenvironment with histone deacetylase inhibitors for more robust and durable T cell responses
Authors: Tyler R. McCaw, Mingyong Liu, Mei Li, Dmytro Starenki, Sara J. Cooper, Rebecca C. Arend, Andres Forero, Donald J. Buchsbaum, Troy D. Randall
Journal: Cancer Research (2018)

Abstract Malignant cells harbor an imbalance in histone acetyltransferase and histone deacetylase (HDAC) activity, epigenetically contributing to altered cellular programs. HDAC inhibitors disrupt this balance to impact both cellular transcription and protein function, changing the phenotype of tumor cells as well as responding immune cells, including tumor-infiltrating T cells. We hypothesized that HDAC inhibition could be used to boost anti-tumor T cell responses through inducing expression of immunomodulatory proteins on tumor cells as well as directly altering the transcriptional programs of tumor-specific T cells. To test this, we treated two murine breast cancer models, TS/A and 4T1, with HDAC inhibitors representing class I specificity, entinostat, or pan-specificity, panobinostat, in vitro and in vivo. Culture of tumor cells with either inhibitor increased surface expression of molecules involved in T cell recognition and stimulation, including MHCI, MHCII, CD74, 41BB, CD40, and ICOSL as well as the T cell chemoattractant CXCL10. Treating tumor-bearing mice with HDAC inhibitor resulted in a significant reduction in tumor growth that was absolutely dependent on adaptive immunity. Using depleting antibodies, we next showed that IFNγ and CD8 T cells, but not CD4 T cells or B cells, are necessary for the anti-tumor effects of entinostat. Interestingly, tumor infiltration of CD4 T cells was reduced following treatment and their effector functions were largely unchanged. However, CD8 T cell infiltration was dramatically increased, as was their production of IFNγ, TNFα, and granzyme B even at later time points. This upregulation of effector function was paralleled by a significant increase in the transcription factor T-bet, while Eomes actually decreased over time, trends opposite those seen in CD8 T cells from vehicle treated tumors and that would suggest entinostat treatment can imprint T cells with a transcriptional program less susceptible to exhaustion. Strikingly, we also found that simply adjusting the timing of entinostat dosing relative to T cell activation could abolish anti-tumor effects or lead to rejection in nearly 50% of mice. These effects corresponded with a significant shift in the responding T cell repertoire. Collectively, our data suggests that HDAC inhibition has important effects on both tumor cells and T cells; specifically, altering tumor cell gene expression leads to a repolarization of the tumor microenvironment more favorable to anti-tumor immunity and reprogramming transcriptional profiles of activated T cells improves effector functions and reduces susceptibility to exhaustion. Thus, appropriately timed administration of HDAC inhibitors may synergistically potentiate current tumor immunotherapies, especially adoptive cellular transfer and T cell reinvigoration strategies. Citation Format: Tyler R. McCaw, Mingyong Liu, Mei Li, Dmytro Starenki, Sara J. Cooper, Rebecca C. Arend, Andres Forero, Donald J. Buchsbaum, Troy D. Randall. Manipulating the breast tumor microenvironment with histone deacetylase inhibitors for more robust and durable T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4700.