靶向 CD206+ 巨噬细胞会破坏关键抗肿瘤免疫轴的建立。

IF 12.6 1区 医学 Q1 IMMUNOLOGY
Journal of Experimental Medicine Pub Date : 2025-01-06 Epub Date: 2024-11-27 DOI:10.1084/jem.20240957
Arja Ray, Kenneth H Hu, Kelly Kersten, Tristan Courau, Nicholas F Kuhn, Itzia Zaleta-Linares, Bushra Samad, Alexis J Combes, Matthew F Krummel
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引用次数: 0

摘要

CD206 是肿瘤相关巨噬细胞(TAMs)假定免疫抑制 "M2 "状态的常见标记物。我们制作了一种新型条件性 CD206 (Mrc1) 基因敲入小鼠,以特异性地观察和/或清除 CD206+ TAMs。早期消耗 CD206+ 巨噬细胞和单核细胞(Mono/Macs)会导致肿瘤中传统 I 型树突状细胞(cDC1)、CD8 T 细胞和 NK 细胞的间接丧失。CD206+ TAMs强烈表达CXCL9,与表达应激反应Spp1的TAMs和未成熟单核细胞形成鲜明对比,后者随着早期耗竭而变得突出。CD206+ TAMs以不同方式吸引活化的CD8 T细胞,CD206耗竭肿瘤中的NK和CD8 T细胞缺乏Cxcr3和支持cDC1的Xcl1及Flt3l表达。破坏这一关键的抗肿瘤轴会降低抗原特异性 T 细胞对小鼠肿瘤的控制能力。在人类癌症中,CD206Replete 而非 CD206Depleted Mono/Mac 基因特征与 CD8 T 细胞、cDC1 和 NK 特征密切相关,并与较好的生存率相关。这些发现否定了将 CD206+"M2-like "巨噬细胞归类为免疫抑制性巨噬细胞的说法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting CD206+ macrophages disrupts the establishment of a key antitumor immune axis.

CD206 is a common marker of a putative immunosuppressive "M2" state in tumor-associated macrophages (TAMs). We made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ TAMs. Early depletion of CD206+ macrophages and monocytes (Mono/Macs) led to the indirect loss of conventional type I dendritic cells (cDC1), CD8 T cells, and NK cells in tumors. CD206+ TAMs robustly expressed CXCL9, contrasting with stress-responsive Spp1-expressing TAMs and immature monocytes, which became prominent with early depletion. CD206+ TAMs differentially attracted activated CD8 T cells, and the NK and CD8 T cells in CD206-depleted tumors were deficient in Cxcr3 and cDC1-supportive Xcl1 and Flt3l expressions. Disrupting this key antitumor axis decreased tumor control by antigen-specific T cells in mice. In human cancers, a CD206Replete, but not a CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, cDC1, and NK signatures and was associated with better survival. These findings negate the unqualified classification of CD206+ "M2-like" macrophages as immunosuppressive.

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来源期刊
CiteScore
26.60
自引率
1.30%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.
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