Abstract 2564: Histone deacetylase 6 is a novel target for enhancing T-cell function during anti-tumor response and tumor-peptide vaccination (2014)

Abstract Histone deacetylases (HDACs) are a family of epigenetic regulators with emerging roles in both tumor and immune system biology. In particular, HDAC6 has been reported to modulate the acetylation HSP90, a regulator of regulatory T-cell (Treg) suppressive activity (de Zoeten, Mol Cel Biol, 2011). Here we report a novel role of HDAC6 in T-cell activation and response against tumor or peptide vaccine. Initially the relative expression of HDAC6 was evaluated in mouse and human T-cells, revealing decreased expression of this HDAC following CD3/CD28 stimulation. To further investigate the role(s) of HDAC6 in T-cell function, an HDAC6KO mouse model was utilized. Characterization of the T-cell compartments of the HDAC6KO mouse model showed a slight, but statistically significant increase in CD4+ T-cell population in the lymph nodes at the expense of a decreased percentage of CD8+ T-cells. Further investigation using isotype-specific HDAC6 inhibitors showed similar results when WT T-cells were activated and treated with an HDAC6 inhibitor. In addition to this population skewing, HDAC6 inhibition led to an enhanced expression of CD69 in WT CD4+ T-cells. This result was reproduced in human CD4+ T-cells, indicating a role of HDAC6 in regulating T-cell activation. To evaluate advantages of HDAC6 inhibition for tumor immunotherapy, melanoma-bearing mice were adoptively transferred with T-cells activated and treated with an HDAC6 inhibitor. Ex vivo analysis of memory T-cell distribution in the lymph nodes demonstrated an increased percent of CD44+CD62L+ T-cells upon HDAC6 inhibition, suggesting a role of HDAC6 in the formation or distribution of memory CD4+ and CD8+ T-cells. In a separate experiment, HDAC6KO mice inoculated with melanoma presented significantly delayed tumor growth. Additionally, in a tumor-peptide vaccination model, HDAC6KO mice displayed a remarkably reduced contraction phase in the antigen-specific CD8+ T-cell compartment when compared to WT mice after peptide vaccine administration. To further evaluate whether these in vivo responses were dependent on T-cells, WT or lympho-deficient, lymphoma-bearing mice were treated with an HDAC6 inhibitor. HDAC6 inhibition led to reduced tumor burden in WT mice, which was absent in lympho-deficient mice, highlighting the importance of lymphocytes in the aforementioned in vivo results. Thus, the role of HDAC6 in regulating immune cells during anti-tumor response appears to be more important than the previously reported role as a regulator of Treg function. The data presented demonstrates a positive effect of HDAC6 in T-cell activation, maintenance of anti-tumor response in vivo and persistence of reactive T-cells following peptide vaccination. The results herein described have revealed an unexplored role of HDAC6 with positive implications for cancer immunotherapy, warranting further investigation. Citation Format: Andressa S. Laino, David M. Woods, Fengdong Cheng, HongWei Wang, Eduardo M. Sotomayor. Histone deacetylase 6 is a novel target for enhancing T-cell function during anti-tumor response and tumor-peptide vaccination. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2564. doi:10.1158/1538-7445.AM2014-2564