Cited by 107Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesProtein Degradation and Inhibitors

An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity

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Zhou, Zhuolong, Van der Jeught, Kevin, Fang, Yuanzhang, Yu, Tao, Li, Yujing, Ao, Zheng, Liu, Sheng, Zhang, Lu +11 more·2021·Nature Biomedical Engineering

Abstract

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.

    “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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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
Venue
Nature Biomedical Engineering
Published
2021-11-01
Volume
5
Issue
11
Pages
1320-1335
ISSN
2157-846X (ISSN-L)
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
Open access
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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