Abstract 3555: Histone deacetylase 6 as a novel regulator of the immunogenicity and aggressiveness of melanoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.3555-3555
• Main 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
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-3555

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 ski