Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Sci Adv. 2024 Nov;10(44):eado8275. doi: 10.1126/sciadv.ado8275. Epub 2024 Oct 30.
Aberrant Notch, which is a defining feature of triple-negative breast cancer (TNBC) cells, regulates intercellular communication in the tumor immune microenvironment (TIME). This includes tumor-associated macrophage (TAM) recruitment through Notch-dependent cytokine secretion, contributing to an immunosuppressive TIME. Despite the low response rate of TNBC to immune checkpoint blockade (ICB), here, we report that inhibition of Notch-driven cytokine-mediated programs reduces TAMs and induces responsiveness to sequentially delivered ICB. This is characterized by the emergence of GrB cytotoxic T lymphocytes (CTLs) in the primary tumor. A more impressive effect of sequential treatment is observed in the lung where TAM depletion and increased CTLs are accompanied by near-complete abolition of metastases. This is due to (i) therapeutic reduction in Notch-dependent, prometastatic circulating factors released by the primary tumor, and (ii) elevated PD ligand 1 (PD-L1) in lung metastases, rendering them profoundly sensitive to ICB. These findings highlight the potential of combination cytokine inhibition and ICB as an immunotherapeutic strategy in TNBC.
异常的 Notch 信号通路是三阴性乳腺癌（TNBC）细胞的一个显著特征，它调节肿瘤免疫微环境（TIME）中的细胞间通讯。这包括通过 Notch 依赖性细胞因子分泌招募肿瘤相关巨噬细胞（TAM），导致 TIME 免疫抑制。尽管 TNBC 对免疫检查点阻断（ICB）的反应率较低，但在这里，我们报告 Notch 驱动的细胞因子介导的程序抑制减少了 TAM，并诱导对顺序给予的 ICB 的反应性。这表现为在原发性肿瘤中出现 GrB 细胞毒性 T 淋巴细胞（CTL）。在肺部观察到序贯治疗更显著的效果，TAM 耗竭和增加的 CTL 伴随着转移的几乎完全消除。这是由于（i）通过原发性肿瘤释放的 Notch 依赖性、促进转移的循环因子的治疗性减少，以及（ii）肺转移中 PD 配体 1（PD-L1）的升高，使它们对 ICB 高度敏感。这些发现强调了联合细胞因子抑制和 ICB 作为 TNBC 的一种免疫治疗策略的潜力。
