Version 1
: Received: 7 November 2024 / Approved: 7 November 2024 / Online: 8 November 2024 (16:55:33 CET)
How to cite:
Bullock, K. K.; Hasaka, T. P.; Days, E.; Bauer, J. A.; Ward, P. A.; Richmond, A. A High-Throughput Immune-Oncology Screen Identifies Immunostimulatory Properties of Cytotoxic Chemotherapy Agents in TNBC. Preprints2024, 2024110535. https://doi.org/10.20944/preprints202411.0535.v1
Bullock, K. K.; Hasaka, T. P.; Days, E.; Bauer, J. A.; Ward, P. A.; Richmond, A. A High-Throughput Immune-Oncology Screen Identifies Immunostimulatory Properties of Cytotoxic Chemotherapy Agents in TNBC. Preprints 2024, 2024110535. https://doi.org/10.20944/preprints202411.0535.v1
Bullock, K. K.; Hasaka, T. P.; Days, E.; Bauer, J. A.; Ward, P. A.; Richmond, A. A High-Throughput Immune-Oncology Screen Identifies Immunostimulatory Properties of Cytotoxic Chemotherapy Agents in TNBC. Preprints2024, 2024110535. https://doi.org/10.20944/preprints202411.0535.v1
APA Style
Bullock, K. K., Hasaka, T. P., Days, E., Bauer, J. A., Ward, P. A., & Richmond, A. (2024). A High-Throughput Immune-Oncology Screen Identifies Immunostimulatory Properties of Cytotoxic Chemotherapy Agents in TNBC. Preprints. https://doi.org/10.20944/preprints202411.0535.v1
Chicago/Turabian Style
Bullock, K. K., Patricia A Ward and Ann Richmond. 2024 "A High-Throughput Immune-Oncology Screen Identifies Immunostimulatory Properties of Cytotoxic Chemotherapy Agents in TNBC" Preprints. https://doi.org/10.20944/preprints202411.0535.v1
Abstract
Triple-negative breast cancers (TNBC) typically have a greater immune cell infiltrate and are more likely to respond to immune checkpoint inhibition (ICI) than ER+ or HER2+ breast cancers. However, there is crucial need to optimize combining chemotherapy strategies with ICI to enhance overall survival TNBC. Therefore, we developed a high-throughput co-culture screening assay to identify compounds enhancing CD8+T-cell-mediated tumor cell cytotoxicity, screening over 400 FDA-approved compounds or agents under investigation for oncology indications. Four chemotherapy agents were chosen as priority hits for mechanistic follow-up due to their ability to enhance T-cell mediated cytotoxicity at multiple doses and multiple timepoints: paclitaxel, bleomycin sulfate, ispinesib and etoposide. Lead compounds affected expression of MHCI, MHCII, and PD-L1, and induced markers of immunogenic cell death (extracellular ATP or HMGB1). Based on ability to increase tumor cell susceptibility to T-cell mediated cytotoxicity, while minimizing T-cell toxicity, bleomycin was identified as the most promising lead candidate. Overall, the results of these studies provide mechanistic insight into potential new chemotherapy partners to enhance anti-PD-1 efficacy in TNBC patients.
Keywords
Breast Cancer; Immune Response; CD8+ T-cells; Cytotoxic Chemotherapy
Subject
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
