Inhibition of Notch enhances efficacy of immune checkpoint blockade in triple-negative breast cancer

Affiliations

• 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.
• Department of Medicine, Division of Medical Oncology, University of Toronto, Toronto, Ontario, Canada.
• Department of Immunology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Room 7205, Toronto, Ontario M5S 1A8, Canada.
• Department of Medical Biophysics, University of Toronto, Toronto Medical Discovery Tower, MaRS Centre, 101 College Street, Room 15-701, Toronto, Ontario M5G 2M9, Canada.
• Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Suite 8-411, Toronto, Ontario M5G 2M9, Canada.

PMID:  39475614  DOI: 10.1126/sciadv.ado8275

Abstract

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.

Notch异常是三阴性乳腺癌（TNBC）细胞的一个特征，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），从而形成免疫抑制性TIME。尽管 TNBC 对免疫检查点阻断（ICB）的反应率很低，但我们在此报告说，抑制 Notch 驱动的细胞因子介导的程序可减少 TAM，并诱导对连续递送的 ICB 产生反应。其特点是原发性肿瘤中出现了 GrB+ 细胞毒性 T 淋巴细胞（CTL）。在肺部观察到的序贯治疗效果更令人印象深刻，TAM 消耗和 CTLs 增加的同时，转移灶几乎完全消失。这是由于：(i) 原发肿瘤释放的Notch依赖性促转移循环因子的治疗性减少；(ii) 肺转移瘤中PD配体1（PD-L1）的升高，使其对ICB极为敏感。这些发现凸显了细胞因子抑制和 ICB 联合疗法作为 TNBC 免疫治疗策略的潜力。

关键词：三阴性乳腺癌，Notch，PD1，PDL1，RMP1-14，VMH02202，InVivo抗体，佰乐博，佰乐博生物