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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Authors | Zhuolong Zhou, Kevin Van der Jeught, Yuanzhang Fang, Tao Yu, Yujing Li, Zheng Ao, Sheng Liu, Lu Zhang, Yang Yang, Haniyeh Eyvani, Mary L Cox, Xiyu Wang, Xiaoming He, Guang Ji, Bryan P Schneider, Feng Guo, Jun Wan, Xinna Zhang, Xiongbin Lu |
Journal | Nature biomedical engineering
(Nat Biomed Eng)
Vol. 5
Issue 11
Pg. 1320-1335
(11 2021)
ISSN: 2157-846X [Electronic] England |
PMID | 34725507
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2021. The Author(s), under exclusive licence to Springer Nature Limited. |
Topics |
- Animals
- Antigen Presentation
- Breast Neoplasms
- CD8-Positive T-Lymphocytes
- Epigenesis, Genetic
- Female
- Humans
- Mice
- Organoids
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