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HDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade
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Abstract
Expression of PD-1 ligands by tumors and interaction with PD-1–expressing T cells in the tumor microenvironment can result in tolerance. Therapies targeting this coinhibitory axis have proven clinically successful in the treatment of metastatic melanoma, non–small cell lung cancer, and other malignancies. Therapeutic agents targeting the epigenetic regulatory family of histone deacetylases (HDAC) have shown clinical success in the treatment of some hematologic malignancies. Beyond direct tumor cell cytotoxicity, HDAC inhibitors have also been shown to alter the immunogenicity and enhance antitumor immune responses. Here, we show that class I HDAC inhibitors upregulated the expression of PD-L1 and, to a lesser degree, PD-L2 in melanomas. Evaluation of human and murine cell lines and patient tumors treated with a variety of HDAC inhibitors in vitro displayed upregulation of these ligands. This upregulation was robust and durable, with enhanced expression lasting past 96 hours. These results were validated in vivo in a B16F10 syngeneic murine model. Mechanistically, HDAC inhibitor treatment resulted in rapid upregulation of histone acetylation of the PD-L1 gene leading to enhanced and durable gene expression. The efficacy of combining HDAC inhibition with PD-1 blockade for treatment of melanoma was also explored in a murine B16F10 model. Mice receiving combination therapy had a slower tumor progression and increased survival compared with control and single-agent treatments. These results highlight the ability of epigenetic modifiers to augment immunotherapies, providing a rationale for combining HDAC inhibitors with PD-1 blockade. Cancer Immunol Res; 3(12); 1375–85. ©2015 AACR.
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“Similar findings have been documented in syngeneic mouse models of melanoma subjected to epigenetic reprogramming with HDAC inhibitors”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Woods et al., 2015
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“HDAC inhibitor combined with α-PD-1/PD-L1 has shown a synergistic antitumor effect in murine tumor models [329–331].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [329]
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Metadata
- Authors
- Woods, D. M., Sodré, A. L., Villagra, A., Sarnaik, A., Sotomayor, E. M., & Weber, J.
- Affiliations
- Moffitt Cancer Center (US)
- Corresponding author
- Sotomayor, Eduardo M.
- Weber, Jeffrey
- Venue
- Cancer Immunology Research
- Published
- 2015-12-01
- Volume
- 3
- Issue
- 12
- Pages
- 1375-1385
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC4674300
- OpenAlex
- W2153162429
- Cited by
- 454
- References
- 47
- Citations by year
- 2026: 33 · 2025: 43 · 2024: 40 · 2023: 51 · 2022: 46 · 2021: 67 · 2020: 42 · 2019: 43 · 2018: 37 · 2017: 32 · 2016: 20
- FWCI
- 12.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Moffitt Cancer Center
- National Institutes of Health (CA168536)
- National Cancer Institute (T32CA115308, K23CA178083, CA168536, P50CA168536, P30CA076292)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- histone deacetylase inhibitors, anti-PD-1 therapy, PD-L1, PD-L2, melanoma, cancer immunotherapy, histone acetylation, epigenetic regulation, tumor microenvironment, combination therapy
- MeSH terms
- Nivolumab, Animals, Antibodies, Monoclonal, Antineoplastic Agents, Histone Deacetylases, Humans, Immunotherapy, Melanoma, Experimental, Mice, Inbred C57BL, Up-Regulation, Cell Line, Tumor, Mice, Histone Deacetylase Inhibitors, Tumor Microenvironment, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Programmed Cell Death 1 Ligand 2 Protein, Antibodies, Monoclonal, Humanized
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