Bullock Kennady K, Hasaka Thomas, Days Emily, Bauer Joshua A, Ward Patricia A, Richmond Ann
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA.
Cancers (Basel). 2024 Dec 5;16(23):4075. doi: 10.3390/cancers16234075.
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. 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. 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). 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.
三阴性乳腺癌（TNBC）通常比雌激素受体阳性（ER+）或人表皮生长因子受体2阳性（HER2+）乳腺癌有更多的免疫细胞浸润，并且更有可能对免疫检查点抑制（ICI）产生反应。然而，迫切需要优化化疗策略与ICI的联合使用，以提高TNBC患者的总生存期。因此，我们开发了一种高通量共培养筛选试验，以鉴定能够增强CD8+T细胞介导的肿瘤细胞细胞毒性的化合物。筛选文库中包括400多种FDA批准的化合物或正在进行肿瘤学适应症研究的药物。由于四种化疗药物在多个剂量和多个时间点均能增强T细胞介导的细胞毒性，因此被选为进行机制后续研究的优先命中药物：紫杉醇、硫酸博来霉素、isopinesib和依托泊苷。先导化合物影响主要组织相容性复合体I类分子（MHCI）、主要组织相容性复合体II类分子（MHCII）和程序性死亡受体配体1（PD-L1）的表达，并诱导免疫原性细胞死亡标志物（细胞外ATP或高迁移率族蛋白B1（HMGB1））。基于在使T细胞毒性最小化的同时增加肿瘤细胞对T细胞介导的细胞毒性的敏感性的能力，博来霉素被确定为最有前景的先导候选药物。总体而言，这些研究结果为增强TNBC患者抗程序性死亡蛋白1（PD-1）疗效的潜在新化疗联合药物提供了机制性见解。
