Carcinoma-associated fibroblasts (CAF) are key players in the tumor microenvironment. Here, we characterize four CAF subsets in breast cancer with distinct properties and levels of activation. Two myofibroblastic subsets (CAF-S1, CAF-S4) accumulate differentially in triple-negative breast cancers (TNBC). CAF-S1 fibroblasts promote an immunosuppressive environment through a multi-step mechanism. By secreting CXCL12, CAF-S1 attracts CD4⁺CD25⁺ T lymphocytes and retains them by OX40L, PD-L2, and JAM2. Moreover, CAF-S1 increases T lymphocyte survival and promotes their differentiation into CD25^HighFOXP3^High, through B7H3, CD73, and DPP4. Finally, in contrast to CAF-S4, CAF-S1 enhances the regulatory T cell capacity to inhibit T effector proliferation. These data are consistent with FOXP3+ T lymphocyte accumulation in CAF-S1-enriched TNBC and show how a CAF subset contributes to immunosuppression.

中文翻译：

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人乳腺癌中的成纤维细胞异质性和免疫抑制环境。

癌相关的成纤维细胞（CAF）是肿瘤微环境中的关键角色。在这里，我们表征了乳腺癌中具有不同特性和激活水平的四个CAF亚群。在三阴性乳腺癌（TNBC）中，两个肌纤维母细胞亚群（CAF-S1，CAF-S4）差异累积。CAF-S1成纤维细胞通过多步机制促进免疫抑制环境。通过分泌CXCL12，CAF-S1会吸引CD4 ⁺ CD25 ⁺ T淋巴细胞，并被OX40L，PD-L2和JAM2保留。此外，CAF-S1增加T淋巴细胞的存活并促进其分化为CD25^高FOXP3^高，通过B7H3，CD73和DPP4。最后，与CAF-S4相反，CAF-S1增强了调节性T细胞抑制T效应子增殖的能力。这些数据与富含CAF-S1的TNBC中的FOXP3 + T淋巴细胞积累一致，并显示了CAF亚群如何促进免疫抑制。