An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity PMID: 34725507

ADC Targets in Oncology

2026-04-10

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

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].

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.