Oncotarget

Research Papers:

HDAC inhibitors enhance the immunotherapy response of melanoma cells

Laurence Booth, Jane L. Roberts, Andrew Poklepovic, John Kirkwood and Paul Dent _

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Oncotarget. 2017; 8:83155-83170. https://doi.org/10.18632/oncotarget.17950

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Abstract

Laurence Booth1, Jane L. Roberts1, Andrew Poklepovic2, John Kirkwood3 and Paul Dent1

1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0035, USA

2Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0035, USA

3University of Pittsburgh Cancer Institute, Melanoma and Skin Cancer Program, Hillman Cancer Research Pavilion Laboratory, Pittsburgh, PA 15232, USA

Correspondence to:

Paul Dent, email: [email protected]

Keywords: melanoma, immunotherapy, HDAC inhibitor, pazopanib, autophagy

Received: March 22, 2017     Accepted: May 03, 2017     Published: May 17, 2017

ABSTRACT

We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney. Knock down of HDAC1, HDAC3, HDAC8 and HDAC10, but not HDAC6, recapitulated the effects of the HDAC inhibitors on the immunotherapy biomarkers. Using B16 mouse melanoma cells we discovered that pre-treatment with AR42 or sodium valproate enhanced the anti-tumor efficacy of an anti-PD-1 antibody and of an anti-CTLA4 antibody. In the B16 model, both AR42 and sodium valproate enhanced the anti-tumor efficacy of the multi-kinase inhibitor pazopanib. In plasma from animals exposed to [HDAC inhibitor + anti-PD-1], but not [HDAC inhibitor + anti-CTLA4], the levels of CCL2, CCL5, CXCL9 and CXCL2 were increased. The cytokine data from HDAC inhibitor plus anti-PD-1 exposed tumors correlated with increased activated T cell, M1 macrophage, neutrophil and NK cell infiltration. Collectively, our data support the use of pan-HDAC inhibitors in combination with kinase inhibitors or with checkpoint inhibitor antibodies as novel melanoma therapeutic strategies.


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