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Updated: Feb 18, 2026
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
HDAC inhibitors enhance the immunotherapy response of melanoma cells
Laurence Booth1, Jane L Roberts1, Andrew Poklepovic2
1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
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.
Insights
Pan-histone deacetylase (HDAC) inhibitors like AR42 and sodium valproate can enhance melanoma immunogenicity. Combining HDAC inhibitors with checkpoint inhibitors or kinase inhibitors shows promise for novel cancer therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Histone deacetylase (HDAC) inhibitors are investigated for cancer treatment.
- Melanoma and other cancers exhibit complex interactions with the immune system.
- Tumor immunogenicity can be modulated to improve therapeutic responses.
Purpose of the Study:
- To evaluate the impact of pan-histone deacetylase (HDAC) inhibitors on melanoma cell immunogenicity.
- To explore the potential of combining HDAC inhibitors with immunotherapy or targeted therapies.
- To identify biomarkers associated with HDAC inhibitor treatment in various cancer types.
Main Methods:
- Treatment of melanoma, ovarian, H&NSCC, lung, and kidney cancer cells with HDAC inhibitors (AR42, sodium valproate).
- Analysis of immunotherapy biomarkers (PD-L1, PD-L2, MHCA) and HDAC protein levels.
- Gene knockdown experiments for specific HDACs (HDAC1, HDAC3, HDAC8, HDAC10).
- In vivo studies using B16 mouse melanoma models treated with HDAC inhibitors combined with anti-PD-1, anti-CTLA4, or pazopanib.
- Cytokine profiling and immune cell infiltration analysis in tumor tissues and plasma.
Main Results:
- HDAC inhibitors reduced PD-L1, PD-L2, and ODC expression while increasing MHCA expression.
- Knockdown of specific HDACs mimicked the effects of HDAC inhibitors on immunotherapy biomarkers.
- Pre-treatment with HDAC inhibitors enhanced the anti-tumor efficacy of anti-PD-1 and anti-CTLA4 antibodies, as well as pazopanib.
- Combination therapy (HDAC inhibitor + anti-PD-1) increased specific cytokines (CCL2, CCL5, CXCL9, CXCL2) and immune cell infiltration (T cells, M1 macrophages, neutrophils, NK cells).
Conclusions:
- Pan-HDAC inhibitors can significantly alter melanoma immunogenicity and enhance responses to immunotherapy and targeted therapies.
- Specific HDACs (HDAC1, HDAC3, HDAC8, HDAC10) play a crucial role in mediating these effects.
- Combination strategies involving HDAC inhibitors offer promising avenues for novel melanoma therapeutic approaches.
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