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 that 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 checkpoint inhibitor programmed-death-1. Standardized measurements of tumour-cell killing activity facilitated by tumour-organoid–T cell screens may aid the identification of candidate immunotherapeutics for a range of cancers.
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