Lipid-Associated Macrophages Are Induced by Cancer-Associated Fibroblasts and Mediate Immune Suppression in Breast Cancer.
Lipid-Associated Macrophages Are Induced by Cancer-Associated Fibroblasts and Mediate Immune Suppression in Breast Cancer.
复制标题
脂质相关巨噬细胞由癌症相关成纤维细胞诱导，并介导乳腺癌中的免疫抑制。
DOI：
10.1158/0008-5472.can-22-1427
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发表时间：
2022
期刊：
影响因子：
11.2
通讯作者：
L
中科院分区：
文献类型：
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作者：
Timperi,Eleonora;Gueguen,Paul;Molgora,Martina;Magagna,Ilaria;Kieffer,Yann;Lopez-Lastra,Silvia;Sirven,Philemon;Baudrin,LauraG;Baulande,Sylvain;Nicolas,André;Champenois,Gabriel;Meseure,Didier;Vincent-Salomon,Anne;Tardivon,Anne;L
肿瘤相关巨噬细胞（TAM）在三阴性乳腺癌（TNBC）中起着有害作用。深入分析TAM的特征及其与间质细胞（如癌症相关成纤维细胞（CAF））的相互作用，可以提供重要的生物学和治疗见解。在这里，我们在单细胞水平上发现了一个单核细胞来源的STAB1+ trem2高脂相关巨噬细胞（LAM）亚群，它具有免疫抑制能力，在免疫检查点阻断（ICB）耐药的患者中扩大。小鼠中这种LAM亚群的基因缺失抑制了TNBC肿瘤的生长。流式细胞术和大量RNA测序数据表明，与tnbc来源的CAFs共培养导致血液单核细胞向免疫抑制性STAB1+ trem2highlam重编程，从而抑制t细胞的活化和增殖。细胞间相互作用模型和体外分析表明，炎症性CXCL12-CXCR4轴在肿瘤部位的caf -髓细胞串扰和单核细胞募集中的作用。综上所述，这些数据提示了一种炎症模型，即通过cf驱动的CXCL12-CXCR4轴募集到肿瘤的单核细胞获得了致蛋白的LAM能力，以支持免疫抑制微环境。本研究发现了一种具有免疫抑制功能的脂质相关巨噬细胞亚群，为三阴性乳腺癌的治疗干预提供了新的线索。
Tumor-associated macrophages (TAM) play a detrimental role in triple-negative breast cancer (TNBC). In-depth analysis of TAM characteristics and interactions with stromal cells, such as cancer-associated fibroblast (CAF), could provide important biological and therapeutic insights. Here we identify at the single-cell level a monocyte-derived STAB1+TREM2highlipid-associated macrophage (LAM) subpopulation with immune suppressive capacities that is expanded in patients resistant to immune checkpoint blockade (ICB). Genetic depletion of this LAM subset in mice suppressed TNBC tumor growth. Flow cytometry and bulk RNA sequencing data demonstrated that coculture with TNBC-derived CAFs led to reprogramming of blood monocytes towards immune suppressive STAB1+TREM2highLAMs, which inhibit T-cell activation and proliferation. Cell-to-cell interaction modeling and assaysin vitrodemonstrated the role of the inflammatory CXCL12–CXCR4 axis in CAF–myeloid cell cross-talk and recruitment of monocytes in tumor sites. Altogether, these data suggest an inflammation model whereby monocytes recruited to the tumor via the CAF-driven CXCL12–CXCR4 axis acquire protumorigenic LAM capacities to support an immunosuppressive microenvironment.SignificanceThis work identifies a novel lipid–associated macrophage subpopulation with immune suppressive functions, offering new leads for therapeutic interventions in triple-negative breast cancer.