Open AccessAn organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity
Author(s) -
Zhuolong Zhou,
Kevin Van der Jeught,
Yunzhang 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
Publication year - 2021
Publication title -
nature biomedical engineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.961
H-Index - 56
ISSN - 2157-846X
DOI - 10.1038/s41551-021-00805-x
Subject(s) - organoid , antigen presentation , cancer research , cytotoxic t cell , cytotoxicity , biology , epigenetics , breast cancer , antigen , immunology , immunosurveillance , immune system , t cell , cancer , microbiology and biotechnology , in vitro , biochemistry , genetics , gene
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.