Abstract 3554: The histone deacetylase inhibitor LBH589 augments anti-tumor immunity through direct effects on tumor and immune cells leading to impaired tumor progression in vivo

Abstract

Abstract Overcoming immune tolerance is critical for the development of effective immunotherapy against cancer. Tumor cells induce tolerance through a variety of modalities including the secretion of IL-10 and TGF-β, the expression of inhibitory ligands, and the generation of cells with regulatory properties. Epigenetic modifiers have gained special attention due to their ability to modify immune regulatory pathways. In this context, a group of chemical compound collectively named histone deacetylase inhibitors (HDACi) have recently been shown to modulate tumor cell immunogenicity, adding a new property to their already well-documented cytotoxic effect against transformed cells. LBH589 is a potent, pan-HDACi that has been used in clinical trials for the treatment of several hematological malignancies. Here, we provide evidence of the anti-melanoma effect of LBH589 through its direct effects upon tumor cells as well as its modulatory effects upon immune cells. Indeed, treatment of human and murine melanoma cells in vitro with LBH589 resulted in inhibition of melanoma proliferation, characterized by cell cycle arrest in G1. Moreover, we found that LBH589 enhances the expression of MHC class I and II molecules on melanoma cells, which is critical for immune recognition. In addition, LBH589 treatment inhibits the production of IL-10, while enhancing the secretion of pro-inflammatory cytokines such as IL-12 and the expression of the costimulatory molecule B7.2 on antigen-presenting cells (APCs). LBH-treated APCs also displayed an enhanced capability to activate naïve antigen-specific T-cells as evidenced by their increased production of IL-2 and IFN-γ. More importantly, LBH589-treated APCs also restored the function of anergic T-cells isolated from tumor bearing mice. Finally, in vivo treatment of B16 melanoma bearing mice with LBH589 resulted in a substantial decrease in tumor growth when compared to vehicle-control treated mice (mean 602mm3 vs. 1316mm3, respectively). In conclusion, the dual ability of the pan-HDACi LBH589 to target both melanoma cells and to enhance anti-tumor immune responses provides the rationale for evaluating this compound either alone or in combination with immune enhancing therapeutic approaches (eg, CTLA4 blockade) for melanoma treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3554. doi:1538-7445.AM2012-3554