The DOI matches its Crossref record; 41 of the 43 references it cites were found in a registry or an index.
EZH2 Inhibitor GSK126 Suppresses Antitumor Immunity by Driving Production of Myeloid-Derived Suppressor Cells
Open accessPublished version of a preprint
Abstract
Abstract Enhancer of zeste homolog (EZH2) is a key epigenetic regulator of gene expression and is frequently overexpressed in various cancer types, suggesting a role in oncogenesis. The therapeutic potential of EZH2 inhibitors is currently being explored, but their effect on antitumor immunity is largely unknown. Here we report that suppressing EZH2 activity using EZH2 inhibitor GSK126 resulted in increased numbers of myeloid-derived suppressor cells (MDSC) and fewer CD4+ and IFNγ+CD8+ T cells, which are involved in antitumor immunity. Addition of a neutralizing antibody against the myeloid differentiation antigen GR-1 or gemcitabine/5-fluorouracil–depleted MDSCs alleviated MDSC-mediated immunosuppression and increased CD4+ and CD8+ T-cell tumor infiltration and GSK126 therapeutic efficacy. Mechanistically, we identified a novel pathway of MDSC production in cancer in which EZH2 inhibition directs myeloid differentiation from primitive hematopoietic progenitor cells. These findings suggest that modulating the tumor immune microenvironment may improve the efficacy of EZH2 inhibitors. Significance: This study uncovers a potential mechanism behind disappointing results of a phase I clinical trial of EZH2 inhibitor GSK126 and identifies a translatable combinational strategy to overcome it.
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“EZH2 inhibition with GSK126 reportedly favors MDSC expansion and immunosuppressive functions”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Huang et al., 2019
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EZH2: a novel target for cancer treatment
Duan, R., Du, W., & Guo, W. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00937-8 · Cited by 980
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“GSK126 was also found to be associated with increased nfiltration MDSCs and fewer CD4 and IFNγCD8 T cells.(396) Muscle-invasive bladder cancer cells with KMD6A and SWI/SNF mutations were more sensitive to an EZH2 inhibitor (EPZ011989), which is mediated by enhanced NK cell-related signaling, resulting in tumor cell di…”
Background
Metadata
- Authors
- Huang, S., Wang, Z., Zhou, J., Huang, J., Zhou, L., Luo, J., Wan, Y. Y., Long, H., & Zhu, B.
- Affiliations
- Army Medical University (CN)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Long, Haixia
- Zhu, Bo
- Venue
- Cancer Research
- Published
- 2019-04-15
- Volume
- 79
- Issue
- 8
- Pages
- 2009-2020
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2911341716
- Cited by
- 185
- References
- 43
- Citations by year
- 2026: 10 · 2025: 28 · 2024: 28 · 2023: 30 · 2022: 29 · 2021: 29 · 2020: 21 · 2019: 9
- FWCI
- 8.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Nature Science Foundation of China (81472648, 81802865, and 81620108023)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- EZH2, GSK126, EZH2 inhibitors, myeloid-derived suppressor cells, antitumor immunity, tumor immune microenvironment, CD4+ T cells, CD8+ T cells, interferon-gamma, Gr-1, hematopoietic progenitor cells, myeloid differentiation, epigenetic regulation, combination therapy
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Myeloid-Derived Suppressor Cells, Animals, Colonic Neoplasms, Female, Humans, Indoles, Mice, Inbred C57BL, Mice, Nude, Pyridones, Tumor Cells, Cultured, Apoptosis, CD8-Positive T-Lymphocytes, Carcinoma, Lewis Lung, Receptors, Chemokine, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Antibodies, Neutralizing
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