Abstract 3555: Histone deacetylase 6 as a novel regulator of the immunogenicity and aggressiveness of melanoma
Authors: Woan Karrune V. , Vazquez Lianet , Rock-Klotz Jennifer , Wang Zi , Cheng Fengdong , Wang Hongwei , Woods David , Sahakian Eva , Perez Patricio , Lienlaf Maritza , Achille Alex , Bergman Joel , Kalin Jay , Gill Ajaypal , Powers John , Marante Danay , Pinilla-Ibarz Javier , Seto Ed , Messina Jane L. , Kozikowski Alan P. , Weber Jeffrey S. , Sotomayor Eduardo M. , Villagra Alejandro 
Published: August 2012

Melanoma is currently the fastest growing cancer in incidence according to the World Health Organization. Currently, few therapies provide significant prolongation of survival for metastatic melanoma. Immunotherapy is an attractive modality with potentially few side effects due to the antigen specificity of adaptive immunity. The latest therapy approved by the FDA for the treatment of melanoma was ipilimumab, an antibody against CTLA-4, a key regulator of T-cell activity; however, this therapy offers modest improvements in overall survival. Overcoming mechanisms of tumor-mediated immune suppression requires targeting multiple pathways. One strategy that has gained attention has been the use of histone deacetylase inhibitors (HDACi). Indeed, HDACi treatment has been shown to augment the expression of immunologically relevant genes such as MHC and costimulatory molecules. Furthermore, we have previously demonstrated inhibition of IL-10, a potent anti-inflammatory cytokine, upon treatment of macrophages with HDACi. However, most studies to date have used pan-HDACi, which inhibit all 11 zinc-dependent HDACs. Therefore, the use of more selective HDACi might be preferable in order to minimize side effects. Herein, we demonstrate that HDAC6 is a molecular target in melanoma. Both pharmacologic and genetic disruption of HDAC6 in B16 murine melanoma cells using HDAC6-selective inhibitors (HDAC6i) and targeted shRNA (HDAC6KD), respectively, led to inhibition of proliferation, characterized by G1 arrest measured by propidium iodine staining for DNA content. Furthermore, treatment with HDAC6i led to enhanced expression of immunologically relevant receptors including MHC I and MHC II. In vivo, subcutaneous injection in wild type mice of HDAC6KD B16 cells led to delayed tumor growth as compared with control cells. However, this effect was abrogated in experiments using SCID mice, which lack T- and B-cells, suggesting a critical immune component for tumor control in vivo. The mechanism(s) by which HDAC6 regulates tumor immunogenicity are yet to be defined. One possible mechanism arises from protein immunoprecipitation studies which demonstrate that HDAC6 interacts with, and potentially regulates of STAT3, an important survival and pathogenic factor in melanoma, which also has implications for immune tolerance. Finally, the expression HDAC6 was found to be upregulated in a majority of melanoma patient tumor biopsies by gene microarray analysis, as compared with normal skin. This observation was supported by immunohistochemically-stained patient melanoma tissue microarray. Taken together, HDAC6 presents as an attractive therapeutic target in melanoma by both delaying tumor growth and conferring a more attractive immune target, providing rationale for the development and use of selective HDAC6i. Moreover, the current availability of HDAC6i enhances the translational implications of this work.

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 3555. doi:1538-7445.AM2012-3555