Semaphorin7A and PD-L1 cooperatively drive immunosuppression during mammary involution and breast cancer.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-05-06 DOI:10.1016/j.celrep.2025.115676

Alan M Elder, Heather R Fairchild, Kelsey T Kines, Lauren M Cozzens, Alexandria R Becks, Jill E Slansky, Steven M Anderson, Traci R Lyons

引用次数: 0

Abstract

Postpartum mammary gland remodeling after a pregnancy/lactation cycle is characterized by mechanisms of cell death and inflammation. Here, we show that SEMA7A promotes PD-L1 expression in immune cells of the mammary tissue during involution. These same phenotypes are mimicked in the microenvironment of SEMA7A-expressing tumors, which partially respond to αPD-1/αPD-L1 treatments in vivo. However, cells that remain after treatment are enriched for SEMA7A expression. Therefore, we tested a monoclonal antibody that directly targets SEMA7A-expressing tumors, in part, by reducing SEMA7A-mediated upregulation of PD-L1. In vivo, the SEMA7A monoclonal antibody reduces tumor growth and/or promotes complete regression of mouse mammary tumors, reduces some immunosuppressive phenotypes in the tumor microenvironment, and restores cytotoxic T cells, suggesting that SEMA7A may be a candidate for immune-based therapy for breast cancer patients.

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Semaphorin7A和PD-L1在乳腺复旧和乳腺癌中协同驱动免疫抑制。

妊娠/哺乳周期后的产后乳腺重塑以细胞死亡和炎症机制为特征。在这里，我们发现SEMA7A促进乳腺组织免疫细胞中PD-L1的表达。这些相同的表型在表达sema7a的肿瘤的微环境中被模拟，这些肿瘤在体内对αPD-1/αPD-L1治疗有部分反应。然而，处理后留下的细胞富含SEMA7A表达。因此，我们测试了一种单克隆抗体，该抗体部分通过降低sema7a介导的PD-L1上调来直接靶向表达sema7a的肿瘤。在体内，SEMA7A单克隆抗体可抑制肿瘤生长和/或促进小鼠乳腺肿瘤的完全消退，降低肿瘤微环境中的一些免疫抑制表型，并恢复细胞毒性T细胞，这表明SEMA7A可能是乳腺癌患者免疫治疗的候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.