2. Academic Validation
  3. An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity

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

  • Nat Biomed Eng. 2021 Nov;5(11):1320-1335. doi: 10.1038/s41551-021-00805-x.
Zhuolong Zhou 1,  Kevin Van der Jeught 1,  Yuanzhang Fang 1,  Tao Yu 1,  Yujing Li 1,  Zheng Ao 2,  Sheng Liu 3,  Lu Zhang 1 4,  Yang Yang 1 5,  Haniyeh Eyvani 1,  Mary L Cox 6,  Xiyu Wang 1,  Xiaoming He 7,  Guang Ji 4,  Bryan P Schneider 6 8,  Feng Guo 2,  Jun Wan 1 3 6,  Xinna Zhang 9 10,  Xiongbin Lu 11 12 13
Affiliations

Affiliations

  • 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 2 Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA.
  • 3 Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 4 Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 5 Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 6 Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 7 Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
  • 8 Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
  • 9 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected].
  • 10 Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected].
  • 11 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected].
  • 12 Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected].
  • 13 Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA. [email protected].
PMID: 34725507 DOI: 10.1038/s41551-021-00805-x
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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