Tumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape
Open accessAbstract
Abstract Poorly inflamed carcinomas do not respond well to immune checkpoint blockade. Converting the tumour microenvironment into a functionally inflamed immune hub would extend the clinical benefit of immune therapy to a larger proportion of cancer patients. Here we show, by using comprehensive single-cell transcriptome, proteome, and immune cell analysis, that Entinostat, a class I histone deacetylase inhibitor, facilitates accumulation of the necrosis-targeted recombinant murine immune-cytokine, NHS-rmIL12, in experimental mouse colon carcinomas and poorly immunogenic breast tumours. This combination therapy reprograms the tumour innate and adaptive immune milieu to an inflamed landscape, where the concerted action of highly functional CD8 + T cells and activated neutrophils drive macrophage M1-like polarization, leading to complete tumour eradication in 41.7%-100% of cases. Biomarker signature of favourable overall survival in multiple human tumor types shows close resemblance to the immune pattern generated by Entinostat/NHS-rmIL12 combination therapy. Collectively, these findings provide a rationale for combining NHS-IL12 with Entinostat in the clinical setting.
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Simply abrogating class I HDAC activity without interference with other epigenetic regulators is sufficient to influence expression of cytokines, chemokines, and other inflammatory signals that remodel immune cell activities.
“Simply abrogating class I HDAC activity without any interference with other epigenetic regulators is sufficient to influence the expression of cytokines, chemokines, and other inflammatory signals that remodel immune cells activities (Hicks et al., 2020;Hicks et al., 2021;Nguyen et al., 2018).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Hicks et al., 2021
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References 66 · Cited by 83
- Authors
- Hicks, K. C., Chariou, P. L., Ozawa, Y., Minnar, C. M., Knudson, K. M., Meyer, T. J., Bian, J., Cam, M., Schlom, J., & Gameiro, S. R.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Schlom, Jeffrey
- ORCID
- Venue
- Nature Communications
- Published
- 2021-08-26
- Volume
- 12
- Issue
- 1
- Pages
- 5151-5151
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8390765
- OpenAlex
- W3194570062
- Cited by
- 83
- References
- 66
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 25 · 2023: 18 · 2022: 18
- FWCI
- 6.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Syndax Pharmaceuticals
- National Institutes of Health
- EMD Serono
- National Cancer Institute (ZIABC010944)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- IL-12, entinostat, histone deacetylase inhibitors, tumor immune microenvironment, tumor immunogenicity, tumor necrosis, CD8+ T cells, neutrophils, M1 macrophage polarization, colon cancer, breast cancer, immune checkpoint blockade, prognostic factors, combination immunotherapy
- MeSH terms
- Animals, Benzamides, Breast Neoplasms, Colonic Neoplasms, Drug Therapy, Combination, Female, Humans, Immunoglobulin G, Immunity, Innate, Macrophages, Mice, Inbred BALB C, Pyridines, Recombinant Fusion Proteins, CD8-Positive T-Lymphocytes, Interleukin-12, Cell Line, Tumor, Mice, Adaptive Immunity, Tumor Microenvironment
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