Cancer-cell derived S100A11 promotes macrophage recruitment in ER+ breast cancer.

IF 6.5 2区 医学 Q1 IMMUNOLOGY
Oncoimmunology Pub Date : 2024-12-31 Epub Date: 2024-11-26 DOI:10.1080/2162402X.2024.2429186
Sanghoon Lee, Youngbin Cho, Yiting Li, Ruxuan Li, Angela Wong Lau, Matthew S Laird, Daniel Brown, Priscilla McAuliffe, Adrian V Lee, Steffi Oesterreich, Ioannis K Zervantonakis, Hatice Ulku Osmanbeyoglu
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引用次数: 0

Abstract

Macrophages are pivotal in driving breast tumor development, progression, and resistance to treatment, particularly in estrogen receptor-positive (ER+) tumors, where they infiltrate the tumor microenvironment (TME) influenced by cancer cell-secreted factors. By analyzing single-cell RNA sequencing data from 25 ER+ tumors, we elucidated interactions between cancer cells and macrophages, correlating macrophage density with epithelial cancer cell density. We identified that S100A11, a previously unexplored factor in macrophage-cancer crosstalk, predicts high macrophage density and poor outcomes in ER+ tumors. We found that recombinant S100A11 enhances macrophage infiltration and migration in a dose-dependent manner. Additionally, in a 3D matrix using a panel of three ER+ breast cancer cell lines, we showed that secreted S100A11 levels from cancer cells were associated with increased monocyte infiltration that subsequently differentiation toward macrophages. Genetic silencing of S100A11 in the S100A11-high T47D cancer cells reduced monocyte infiltration, consistent with results using a S100A11 blocking antibody in T47D cancer cells and in a clinically relevant patient-derived organoid model. Phenotypic analysis of macrophages cocultured with T47D cancer cells following S100A11 knockdown revealed lower expression of the immunosuppressive marker CD206, further underscoring the role of S100A11 as a paracrine regulator of pro-tumorigenic cancer-macrophage crosstalk. This study offers novel insights into the interplay between macrophages and cancer cells in ER+ breast tumors, highlighting S100A11 as a potential therapeutic target to modulate the macrophage-rich tumor microenvironment.

癌细胞衍生的 S100A11 可促进 ER+ 乳腺癌巨噬细胞的招募。
巨噬细胞在推动乳腺肿瘤发生、进展和耐药性方面起着关键作用,尤其是在雌激素受体阳性(ER+)肿瘤中,它们会渗透到受癌细胞分泌因子影响的肿瘤微环境(TME)中。通过分析25个ER+肿瘤的单细胞RNA测序数据,我们阐明了癌细胞与巨噬细胞之间的相互作用,并将巨噬细胞密度与上皮癌细胞密度联系起来。我们发现,S100A11是以前未曾探索过的巨噬细胞与癌症相互影响的因素,它能预测ER+肿瘤中的高巨噬细胞密度和不良预后。我们发现重组 S100A11 能以剂量依赖的方式增强巨噬细胞的浸润和迁移。此外,在使用三种ER+乳腺癌细胞系的三维基质中,我们发现癌细胞分泌的S100A11水平与单核细胞浸润的增加有关,而单核细胞浸润后会向巨噬细胞分化。在 S100A11 高的 T47D 癌细胞中基因沉默 S100A11 可减少单核细胞浸润,这与在 T47D 癌细胞中使用 S100A11 阻断抗体以及在临床相关的患者衍生类器官模型中的结果一致。在敲除 S100A11 后,与 T47D 癌细胞共培养的巨噬细胞的表型分析表明,免疫抑制标志物 CD206 的表达较低,这进一步强调了 S100A11 在促肿瘤性癌症-巨噬细胞串联过程中的旁分泌调节因子作用。这项研究为了解ER+乳腺肿瘤中巨噬细胞与癌细胞之间的相互作用提供了新的视角,突出了S100A11作为调节巨噬细胞丰富的肿瘤微环境的潜在治疗靶点的作用。
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
Oncoimmunology
Oncoimmunology ONCOLOGYIMMUNOLOGY-IMMUNOLOGY
CiteScore
12.50
自引率
2.80%
发文量
276
审稿时长
24 weeks
期刊介绍: OncoImmunology is a dynamic, high-profile, open access journal that comprehensively covers tumor immunology and immunotherapy. As cancer immunotherapy advances, OncoImmunology is committed to publishing top-tier research encompassing all facets of basic and applied tumor immunology. The journal covers a wide range of topics, including: -Basic and translational studies in immunology of both solid and hematological malignancies -Inflammation, innate and acquired immune responses against cancer -Mechanisms of cancer immunoediting and immune evasion -Modern immunotherapies, including immunomodulators, immune checkpoint inhibitors, T-cell, NK-cell, and macrophage engagers, and CAR T cells -Immunological effects of conventional anticancer therapies.
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