Melanoma is the deadliest skin cancer, and its incidence has been increasing faster than any other cancer. Although immunogenic, melanoma is not effectively cleared by host immunity. In this study, we investigate the therapeutic, antimelanoma potential of the histone deacetylase inhibitor (HDACi) panobinostat (LBH589) by assessing both its cytotoxic effects on melanoma cells as well as enhancement of immune recognition of melanoma. Utilizing murine and human melanoma cell lines, we analyzed the effects of LBH589 on proliferation and survival. In addition, we analyzed the expression of several immunologically relevant surface markers and melanoma differentiation antigens, and the ability of LBH589-treated melanoma to activate antigen-specific T cells. Finally, we assessed the in-vivo effects of LBH589 in a mouse melanoma model. Low nanomolar concentrations of LBH589 inhibit the growth of all melanoma cell lines tested, but not normal melanocytes. This inhibition is characterized by increased apoptosis as well as a G1 cell cycle arrest. In addition, LBH589 augments the expression of major histocompatibility complex and costimulatory molecules on melanoma cells leading to an increased ability to activate antigen-specific T cells. Treatment also increases expression of melanoma differentiation antigens. In vivo, LBH589 treatment of melanoma-bearing mice results in a significant increase in survival. However, in immunodeficient mice, the therapeutic effect of LBH589 is lost. Taken together, LBH589 exerts a dual effect upon melanoma cells by affecting not only growth/survival but also by increasing melanoma immunogenicity. These effects provide the framework for future evaluation of this HDAC inhibitor in melanoma treatment.
Departments of aImmunology
cMolecular Oncology, H. Lee Moffitt Cancer and Research Institute
dDepartment of Cutaneous Oncology and the Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer and Research Institute
eDepartment of Molecular Medicine, Morsani College of Medicine, Tampa
fCollege of Medicine at the University of South Florida, Gainesville, Florida
gNovartis Pharmaceuticals, East Hanover, New Jersey, USA
*David M. Woods and Karrune Woan: Co-first authors.
Correspondence to Alejandro Villagra, PhD, Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA Tel: +1 813 745 6333; fax: +1 813 745 6817; e-mail: email@example.com
Received May 20, 2013
Accepted July 1, 2013