A High-Throughput Immune-Oncology Screen Identifies Immunostimulatory Properties of Cytotoxic Chemotherapy Agents in TNBC.

IF 4.5 2区 医学 Q1 ONCOLOGY Cancers Pub Date : 2024-12-05 DOI:10.3390/cancers16234075
Kennady K Bullock, Thomas Hasaka, Emily Days, Joshua A Bauer, Patricia A Ward, Ann Richmond
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引用次数: 0

Abstract

Background: Triple-negative breast cancers (TNBCs) 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 a crucial need to optimize combining chemotherapy strategies with ICI to enhance overall survival in TNBC. Methods: Therefore, we developed a high-throughput co-culture screening assay to identify compounds that enhance CD8+ T-cell-mediated tumor cell cytotoxicity. Over 400 FDA-approved compounds or agents under investigation for oncology indications were included in the screening library. Results: 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 time points: paclitaxel, bleomycin sulfate, ispinesib, and etoposide. Lead compounds affected the expression of MHCI, MHCII, and PD-L1 and induced markers of immunogenic cell death (extracellular ATP or HMGB1). Conclusions: Based on the 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.

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高通量免疫肿瘤学筛选发现 TNBC 细胞毒性化疗药物的免疫刺激特性
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来源期刊
Cancers
Cancers Medicine-Oncology
CiteScore
8.00
自引率
9.60%
发文量
5371
审稿时长
18.07 days
期刊介绍: Cancers (ISSN 2072-6694) is an international, peer-reviewed open access journal on oncology. It publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
期刊最新文献
Correction: De Sanctis et al. Lck Function and Modulation: Immune Cytotoxic Response and Tumor Treatment More Than a Simple Event. Cancers 2024, 16, 2630. Contrastive Clustering-Based Patient Normalization to Improve Automated In Vivo Oral Cancer Diagnosis from Multispectral Autofluorescence Lifetime Images. Classification and Prognostic Stratification Based on Genomic Features in Myelodysplastic and Myeloproliferative Neoplasm- and Their Overlapping Conditions. Oncologic Outcomes in Patients with Localized, Primary Head and Neck Synovial Sarcoma. Implications of Clonal Hematopoiesis in Hematological and Non-Hematological Disorders.
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