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+TREM2high lipid-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+TREM2high LAMs, which inhibit T-cell activation and proliferation. Cell-to-cell interaction modeling and assays in vitro demonstrated 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. Significance: This work identifies a novel lipid–associated macrophage subpopulation with immune suppressive functions, offering new leads for therapeutic interventions in triple-negative breast cancer.

中文翻译：

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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

肿瘤相关巨噬细胞（TAM）在三阴性乳腺癌（TNBC）中发挥着有害作用。深入分析 TAM 特征以及与癌症相关成纤维细胞 (CAF) 等基质细胞的相互作用，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鉴定了单核细胞衍生的 STAB1+TREM2 高脂质相关巨噬细胞 (LAM) 亚群，其具有免疫抑制能力，该亚群在对免疫检查点阻断 (ICB) 耐药的患者中得到扩展。小鼠体内 LAM 子集的基因缺失抑制了 TNBC 肿瘤的生长。流式细胞术和批量 RNA 测序数据表明，与 TNBC 衍生的 CAF 共培养导致血液单核细胞重新编程为免疫抑制性 STAB1+TREM2high LAM，从而抑制 T 细胞活化和增殖。细胞间相互作用模型和体外测定证明了炎症 CXCL12-CXCR4 轴在 CAF-骨髓细胞串扰和肿瘤部位单核细胞募集中的作用。总而言之，这些数据表明了一种炎症模型，通过 CAF 驱动的 CXCL12-CXCR4 轴招募到肿瘤的单核细胞获得促肿瘤 LAM 能力，以支持免疫抑制微环境。意义：这项工作确定了一种具有免疫抑制功能的新型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。这些数据表明了一种炎症模型，通过 CAF 驱动的 CXCL12-CXCR4 轴招募到肿瘤的单核细胞获得促肿瘤 LAM 能力，以支持免疫抑制微环境。意义：这项工作确定了一种具有免疫抑制功能的新型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。这些数据表明了一种炎症模型，通过 CAF 驱动的 CXCL12-CXCR4 轴招募到肿瘤的单核细胞获得促肿瘤 LAM 能力，以支持免疫抑制微环境。意义：这项工作确定了一种具有免疫抑制功能的新型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。