Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity
Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity
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DOI：
10.1136/jitc-2020-001008
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Price, Richard J.
中科院分区：
文献类型：
--
作者：
Sheybani, Natasha D.;Witter, Alexandra R.;Price, Richard J.
背景：三阴性乳腺癌(TNBC)仍然是大多数靶向治疗方法的顽固性病例。然而，最近的临床研究表明，诱导肿瘤损伤可以使TNBC对免疫治疗产生反应。因此，我们测试了一种通过聚焦超声(FUS)热消融和化疗吉西他滨(GEM)相结合的方法对小鼠TNBC(4T1肿瘤)进行免疫增敏的策略，吉西他滨可减弱髓系来源的抑制细胞(MDSCs)。方法我们在肿瘤部位应用稀疏扫描热消融FUS方案，并结合全身应用GEM。我们用流式细胞术分析了单一治疗和联合治疗在调节局部和系统免疫中的作用。我们还在Rag1(-/-)小鼠或T细胞耗尽的野生型小鼠身上测试了这种组合，以确定适应性免疫的重要性。此外，我们将程序性细胞死亡蛋白1(PD-1)阻断在这种组合上，以评估其对肿瘤生长和生存的影响。结果FUS单一治疗的免疫调节作用不足以促进针对4T1的强大T细胞应答，这与在该模型中明显的MDSC驱动的免疫抑制是一致的。FUS+GEM的组合显著抑制了原发TNBC肿瘤的生长，延长了小鼠的总体生存时间。肿瘤控制与循环中经历抗原的T细胞的增加有关，完全依赖于T细胞介导的免疫。FUS+GEM控制原发肿瘤生长的能力通过新佐剂或抗PD-1佐剂治疗而适度增强。结论热消融FUS联合GEM可抑制小鼠转移性TNBC模型的原发肿瘤生长，提高生存率和免疫原性。这一治疗策略有望为增强FUS在转移性TNBC免疫治疗中的作用提供一种新的选择，并值得未来的临床评估。
Background Triple-negative breast cancer (TNBC) remains recalcitrant to most targeted therapy approaches. However, recent clinical studies suggest that inducing tumor damage can render TNBC responsive to immunotherapy. We therefore tested a strategy for immune sensitization of murine TNBC (4T1 tumors) through combination of focused ultrasound (FUS) thermal ablation and a chemotherapy, gemcitabine (GEM), known to attenuate myeloid-derived suppressor cells (MDSCs). Methods We applied a sparse-scan thermally ablative FUS regimen at the tumor site in combination with systemically administered GEM. We used flow cytometry analysis to investigate the roles of monotherapy and combinatorial therapy in mediating local and systemic immunity. We also tested this combination in Rag1(-/-)mice or T cell-depleted wild-type mice to determine the essentiality of adaptive immunity. Further, we layered Programmed cell death protein 1 (PD-1) blockade onto this combination to evaluate its impact on tumor outgrowth and survival. Results The immune-modulatory effect of FUS monotherapy was insufficient to promote a robust T cell response against 4T1, consistent with the dominant MDSC-driven immunosuppression evident in this model. The combination of FUS+GEM significantly constrained primary TNBC tumor outgrowth and extended overall survival of mice. Tumor control correlated with increased circulating antigen-experienced T cells and was entirely dependent on T cell-mediated immunity. The ability of FUS+GEM to control primary tumor outgrowth was moderately enhanced by either neoadjuvant or adjuvant treatment with anti-PD-1. Conclusion Thermally ablative FUS in combination with GEM restricts primary tumor outgrowth, improves survival and enhances immunogenicity in a murine metastatic TNBC model. This treatment strategy promises a novel option for potentiating the role of FUS in immunotherapy of metastatic TNBC and is worthy of future clinical evaluation.