DataSheet_1_IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer.pdf

Due to lack of targetable receptors and intertumoral heterogeneity, triple negative breast cancer (TNBC) remains particularly difficult to treat. Doxorubicin (DOX) is typically used as nonselective neoadjuvant chemotherapy, but the diversity of treatment efficacy remains unclear. Comparable to variability in clinical response, an experimental model of TNBC using a 4T1 syngeneic mouse model was found to elicit a differential response to a seven-day treatment regimen of DOX. Single-cell RNA sequencing identified an increase in T cells in tumors that responded to DOX treatment compared to tumors that continued to grow uninhibited. Additionally, compared to resistant tumors, DOX sensitive tumors contained significantly more CD4 T helper cells (339%), γδ T cells (727%), Naïve T cells (278%), and activated CD8 T cells (130%). Furthermore, transcriptional profiles of tumor infiltrated T cells in DOX responsive tumors revealed decreased exhaustion, increased chemokine/cytokine expression, and increased activation and cytotoxic activity. γδ T cell derived IL-17A was identified to be highly abundant in the sensitive tumor microenvironment. IL-17A was also found to directly increase sensitivity of TNBC cells in combination with DOX treatment. In TNBC tumors sensitive to DOX, increased IL-17A levels lead to a direct effect on cancer cell responsiveness and chronic stimulation of tumor infiltrated T cells leading to improved chemotherapeutic efficacy. IL-17A’s role as a chemosensitive cytokine in TNBC may offer new opportunities for treating chemoresistant breast tumors and other cancer types.

鉴于靶向受体的缺失及肿瘤间的异质性，三阴性乳腺癌（TNBC）的治疗尤为棘手。多柔比星（DOX）通常用作非选择性的新辅助化疗，但其疗效的多样性尚不明确。与临床反应的变异性相当，利用4T1同基因小鼠模型构建的TNBC实验模型发现，对为期七天的DOX治疗方案产生了不同的反应。单细胞RNA测序发现，与持续生长不受抑制的肿瘤相比，对DOX治疗产生反应的肿瘤中T细胞数量增加。此外，与耐药肿瘤相比，对DOX敏感的肿瘤中显著含有更多的CD4辅助T细胞（339%）、γδ T细胞（727%）、未成熟T细胞（278%）和激活的CD8 T细胞（130%）。进一步地，对DOX敏感肿瘤中浸润肿瘤的T细胞的转录组分析揭示了耗竭的减少、趋化因子/细胞因子表达的增多以及激活和细胞毒活性的增强。γδ T细胞衍生的IL-17A在敏感的肿瘤微环境中被发现高度富集。IL-17A还发现与DOX治疗联合使用时，可直接增加TNBC细胞的敏感性。在DOX敏感的TNBC肿瘤中，IL-17A水平的增加直接影响了癌细胞对治疗的反应性，并慢性刺激肿瘤浸润的T细胞，从而提高了化疗的疗效。IL-17A在TNBC中作为化疗敏感性细胞因子的作用，可能为治疗化疗耐药的乳腺癌及其他癌症类型提供了新的治疗机会。