Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity
Open accessAbstract
Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8 + and CD4 + effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity.
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The balance of CD4+ Th1, Th2, Th17, and Treg cells can shift dramatically following therapy, with reprogramming from one CD4+ T cell subset to another.
“The balance of CD4+ Th1, Th2, Th17 and Treg cells can shift dramatically following therapy, with reprogramming from one CD4+ T cell subset towards another368,369 (Figure 4).”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [369]
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- Authors
- Wang, D., Quiros, J., Mahuron, K., Pai, C.-C., Ranzani, V., Young, A., Silveria, S., Harwin, T., Abnousian, A., Pagani, M., Rosenblum, M. D., Van Gool, F., Fong, L., Bluestone, J. A., & DuPage, M.
- Affiliations
- University of California, San Francisco (US)
- Istituto Nazionale Genetica Molecolare (IT)
- University of California, Berkeley (US)
- University of Milan (IT)
- Corresponding author
- Bluestone, Jeffrey A.
- DuPage, Michel
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 23
- Issue
- 11
- Pages
- 3262-3274
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6094952
- OpenAlex
- W2808497725
- Cited by
- 318
- References
- 54
- Citations by year
- 2026: 34 · 2025: 36 · 2024: 43 · 2023: 43 · 2022: 43 · 2021: 47 · 2020: 40 · 2019: 24 · 2018: 8
- FWCI
- 12.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Frank A. Campini Foundation
- Parker Institute for Cancer Immunotherapy
- Helen Hay Whitney Foundation
- National Institutes of Health (UM1 AI-12-059, R01 AI046643)
- Associazione Italiana per la Ricerca sul Cancro (IG2013-ID14596)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- EZH2, regulatory T cells, tumor-infiltrating T cells, H3K27 methylation, histone methyltransferase, Treg reprogramming, tumor microenvironment, antitumor immunity, CD8+ T cells, CD4+ T cells, autoimmunity, cancer immunotherapy
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Humans, Interferon-gamma, Mice, Inbred C57BL, Neoplasms, Tumor Necrosis Factor-alpha, CD4-Positive T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Mice, Knockout, CD8-Positive T-Lymphocytes, Cell Line, Tumor, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Tumor Microenvironment
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