Abstract 692: Histone deacetylase 11 is an epigenetic regulator of CD8+ T-cell effector function and memory formation.
Authors: Woods David M. , Woan Karrune , Cheng Fengdong , Wang Hong Wei , Sahakian Eva , Powers John , Rock-Klotz Jennifer , Villagra Alejandro , Pinilla-Ibarz Javier , Sotomayor Eduardo 
Published: August 2014

Cytotoxic T-cells play a vital role in immune mediated tumor responses. Indeed, adoptive transfer of CD8+ T-cells can result in regression of tumor in refractory, progressive metastatic melanoma in a minority of patients (Chapuis, Thompson et al. 2012). In adoptive transfer recipients, clinical response correlates with the persistence of T-cells. Central memory CD8+ T-cells (Tcm) are a population of long-lived T-cells with an enhanced replicative capacity. Resultantly, adoptive transfers of Tcm populations confer a superior anti-melanoma response in mouse models (Klebanoff, Gattinoni et al. 2005). To improve upon the efficacy of T-cell adoptive immunotherapy a more extensive understanding of the mechanisms regulating the formation of central memory cells as well as the effector function and proliferative capacity of CD8+ T-cells is needed. Here we report that the newest discovered histone deacetylase (HDAC), HDAC11, is a negative regulator of Eomes, a transcription factor controlling memory formation and effector phenotype in CD8+ T-cells (Pearce, Mullen et al. 2003; Intlekofer, Takemoto et al. 2005). T-cells from HDAC11 knockout (HDAC11KO) mice demonstrate a robust proliferative capacity upon stimulation when compared to wild-type CD8+ T-cells. Additionally, these cells favor a more robust inflammatory phenotype, producing significantly higher levels of INF-γ, IL-2 and TNF. Analysis of the thymus, spleen and lymph nodes from HDAC11KO mice demonstrates no gross differences in overall percentages or numbers of CD4+ or CD8+ T-cells, nor double positive or double negative thymocytes. However, further examination reveals a significantly increased percentage of Tcm cells in the CD8+ compartment. To further understand these phenotypic differences, we investigated the expression and acetylation of the transcription factor Eomes message. Significantly higher levels of Eomes, both at the basal state and post stimulation, are expressed in HDAC11KO CD8+ T-cells. Additionally, increased levels of acetylated histone 3 at the Eomes promoter, a marker for transcriptional activation, are seen. Finally, in vivo, adoptive transfer of HDAC11KO T-cells results in significantly decreased tumor progression in mice with established melanoma tumors. These results demonstrate HDAC11 as a negative regulator of Eomes expression and, resultantly, a negative regulator of central memory formation and effector function in CD8+ T-cells. Therefore, HDAC11 represents a novel therapeutic target for augmenting the efficacy of T-cell adoptive immunotherapy.

Citation Format: David M. Woods, Karrune Woan, Fengdong Cheng, Hong Wei Wang, Eva Sahakian, John Powers, Jennifer Rock-Klotz, Alejandro Villagra, Javier Pinilla-Ibarz, Eduardo Sotomayor. Histone deacetylase 11 is an epigenetic regulator of CD8+ T-cell effector function and memory formation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 692. doi:10.1158/1538-7445.AM2013-692