Epigenetic modulation of CD1d-mediated antigen presentation by B cell lymphomas (TUM10P.1054)

Abstract

Abstract Histone deacetylases (HDACs) are a family of enzymes that regulate diverse cellular events such as gene expression, cell proliferation, and immune pathways through deacetylation of their protein targets. 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. We examined CD1d-mediated antigen presentation to NKT cells following treatment with HDAC inhibitors (HDACi). Consistent with previous studies, we found that preventing deacetylation by treatment with Trichostatin A, a pan-HDACi, enhanced both CD1d and MHC class II-mediated antigen presentation. Similarly, treatment of B cell lymphomas with Panobinostat resulted in increased CD1d-dependent NKT cell responses, due at least in part to a dose-dependent increase in CD1d-cell surface expression. In addition, treatment with HDCAi results in a decrease in STAT3 expression as well as IL-10 secretion by B cell lymphomas. Overall, our studies demonstrate the efficacy of HDACi in restoring anti-tumor responses to B cell lymphomas through both cell-intrinsic and extrinsic factors. Collectively, these results suggest that HDACi may work to enhance the immune response and increases the immunogenicity of the tumor itself.