HDAC inhibitors enhance CD1d-dependent NKT cell responses to lymphoma

Abstract

Abstract Histone deacetylases (HDACs) influence expression of genes implicated in tumor initiation, progression and anti-tumor responses. We hypothesize that tumors use epigenetic mechanisms to dysregulate CD1d-mediated antigen processing and presentation, which leads to a functional impairment in the ability of Natural killer T (NKT) cells to recognize and destroy cancerous cells. In this study, we treated CD1d-expressing tumor cells with HDAC inhibitors (HDACi) to assess CD1d-dependent NKT cell responses to B cell lymphoma. Consistent with previous studies, we found that treatment with Trichostatin A, a pan-HDACi, enhanced both CD1d and MHC class II-mediated antigen presentation. Similarly, treatment of B cell lymphomas with other HDACi, Panobinostat and Vorinostat, resulted in enhanced CD1d-dependent NKT cell responses. Mechanistically, we found that HDAC2 binds to the CD1d promoter and knockdown of HDAC2 in tumor cells enhanced their immunogenicity. The observed changes are due at least in part to a dose-dependent increase in both CD1d mRNA and CD1d cell surface expression. In addition, treatment with HDCAi resulted in a decrease in inflammatory cytokine secretion by B cell lymphomas. To examine the therapeutic potential of HDACi, we treated human peripheral blood mononuclear cells with TSA and Panobinostat. Treatment with these HDACi did not suppress T cell activation; conversely, treatment with a novel HDAC4 inhibitor MC1568 suppressed T cell responses. Taken together, our studies demonstrate the efficacy of HDACi in restoring anti-tumor responses to B cell lymphomas through both cell-intrinsic and extrinsic factors and strongly implicate a role for select HDACi in cancer immunotherapeutic strategies.