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.
背景：与ER阳性或HER2阳性乳腺癌相比，三阴性乳腺癌（TNBC）通常具有更强的免疫细胞浸润，且更可能对免疫检查点抑制剂（ICI）产生应答。然而，优化化疗策略与ICI的联合应用以提升TNBC患者的总生存率至关重要。 方法：为此，我们开发了一种高通量共培养筛选方法，旨在识别能够增强CD8+ T细胞介导的肿瘤细胞毒性的化合物。筛选库中包含了400多种已获FDA批准或正在研究的肿瘤适应症药物。 结果：四种化疗药物因其在多个剂量和时间点均能增强T细胞介导的细胞毒性而被选为优先研究对象进行机制性后续研究：紫杉醇、硫酸博来霉素、ispinesib和依托泊苷。这些先导化合物影响了MHCI、MHCII和PD-L1的表达，并诱导了免疫原性细胞死亡标志物（如细胞外ATP或HMGB1）的产生。 结论：基于在最小化T细胞毒性的同时增强肿瘤细胞对T细胞介导的细胞毒性的敏感性，博来霉素被确定为最有前景的先导候选药物。总体而言，这些研究结果为探索增强TNBC患者抗PD-1疗效的潜在新型化疗联合方案提供了机制性见解。
肿瘤(癌症)患者之家