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An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity
Open accessAbstract
In breast cancer, genetic heterogeneity, the lack of actionable targets and immune evasion all contribute to the limited clinical response rates to immune checkpoint blockade therapy. Here, we report a high-throughput screen based on the functional interaction of mouse- or patient-derived breast tumour organoids and tumour-specific cytotoxic T cells for the identification of epigenetic inhibitors that promote antigen presentation and potentiate T-cell-mediated cytotoxicity. We show that the epigenetic inhibitors GSK-LSD1, CUDC-101 and BML-210, identified by the screen, display antitumour activities in orthotopic mammary tumours in mice, that they upregulate antigen presentation mediated by the major histocompatibility complex class I on breast tumour cells and that treatment with BML-210 substantially sensitized breast tumours to the inhibitor of the checkpoint programmed death-1. Standardized measurements of tumour-cell killing activity facilitated by tumour-organoid-T-cell screens may help with the identification of candidate immunotherapeutics for a range of cancers.
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“A high-throughput screening, based on the interaction between patient-derived breast cancer organoids and tumor-specific cytotoxic T cells, identified three epigenetic inhibitors - BML-210, GSK-LSD1, and CUDC-101—that displayed significant antitumor effects.44”
From Drug repurposing for cancer therapy (2024) · cites this paper as [44]
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Metadata
- Authors
- Zhou, Z., Van der Jeught, K., Fang, Y., Yu, T., Li, Y., Ao, Z., Liu, S., Zhang, L., Yang, Y., Eyvani, H., Cox, M. L., Wang, X., He, X., Ji, G., Schneider, B. P., Guo, F., Wan, J., Zhang, X., & Lu, X.
- Affiliations
- Indiana University Indianapolis (US)
- Indiana University Bloomington (US)
- Shanghai University of Traditional Chinese Medicine (CN)
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center (US)
- University of Maryland, College Park (US)
- Corresponding author
- Zhang, Lu
- Zhang, Xinna
- Lu, Xiongbin
- ORCID
- Venue
- Nature Biomedical Engineering
- Published
- 2021-11-01
- Volume
- 5
- Issue
- 11
- Pages
- 1320-1335
- ISSN
- 2157-846X (ISSN-L)
- PMC
- PMC8647932
- OpenAlex
- W3210520893
- Cited by
- 107
- References
- 75
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 28 · 2023: 26 · 2022: 16 · 2021: 3
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Update notices
- correction (2023-08-30)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Biomedical Engineering (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (CA206366, CA243023, CA203737, CA222251)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- breast cancer, tumor organoids, epigenetic inhibitors, antigen presentation, MHC class I, T cell cytotoxicity, immune checkpoint blockade, PD-1, CUDC-101, high-throughput screening, immunotherapy, tumor immune evasion
- MeSH terms
- Animals, Breast Neoplasms, Female, Humans, Organoids, Antigen Presentation, CD8-Positive T-Lymphocytes, Epigenesis, Genetic, Mice
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