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Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses
Published on: May 6, 2019
An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated
Zhuolong Zhou1, Kevin Van der Jeught1, Yuanzhang Fang1
1Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
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.
Insights
New epigenetic inhibitors enhance breast cancer antigen presentation and T-cell killing. These compounds, identified via organoid screening, show promise in sensitizing tumors to immune checkpoint blockade therapy.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Breast cancer exhibits limited response to immune checkpoint blockade due to genetic heterogeneity, lack of targets, and immune evasion.
- Identifying novel therapeutic strategies is crucial to improve treatment efficacy.
Purpose of the Study:
- To identify epigenetic inhibitors that enhance antigen presentation and T-cell-mediated cytotoxicity in breast cancer.
- To evaluate the efficacy of identified inhibitors in preclinical models and their potential to overcome resistance to immune checkpoint blockade.
Main Methods:
- A high-throughput screen utilizing functional interactions between breast tumor organoids and cytotoxic T cells.
- Assessment of epigenetic inhibitors (GSK-LSD1, CUDC-101, BML-210) in orthotopic mouse models.
- Evaluation of major histocompatibility complex class I (MHC-I) upregulation and T-cell-mediated tumor cell killing.
Main Results:
- The screen identified GSK-LSD1, CUDC-101, and BML-210 as epigenetic inhibitors with anti-tumor activity.
- These inhibitors upregulated MHC-I expression on breast tumor cells, enhancing antigen presentation.
- BML-210 treatment sensitized breast tumors to anti-programmed death-1 (PD-1) therapy.
Conclusions:
- Epigenetic inhibitors can enhance anti-tumor immunity by promoting antigen presentation and T-cell cytotoxicity.
- Tumor-organoid-T-cell screens are valuable for identifying novel immunotherapeutic candidates.
- Targeting epigenetic mechanisms offers a promising strategy to improve responses to immune checkpoint blockade in breast cancer.
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