Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer
Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer
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DOI：
10.1016/j.ccell.2018.01.011
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发表时间：
2018-03-12
期刊：
影响因子：
50.3
通讯作者：
Mechta-Grigoriou, Fatima
中科院分区：
文献类型：
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作者：
Costa, Ana;Kieffer, Yann;Mechta-Grigoriou, Fatima
肿瘤相关成纤维细胞(CAF)是肿瘤微环境中的关键分子。在这里，我们描述了乳腺癌中的四个CAF亚群，它们具有不同的特性和激活水平。在三阴性乳腺癌(TNBC)中，两个肌成纤维细胞亚群(CAF-S1、CAF-S4)不同地聚集。CAF-S1成纤维细胞通过多步骤机制促进免疫抑制环境。通过分泌CXCL12，CAF-S1可以吸引CD4(+)CD25(+)T淋巴细胞，并通过OX40L、PD-L2和JAM2保留它们。此外，CAF-S1通过B7H3、CD73和DPP4增加T淋巴细胞的存活率，并促进其分化为CD25(高)FOXP3(高)。最后，与CAF-S4相比，CAF-S1增强了调节性T细胞抑制T效应器增殖的能力。这些数据与FOXP3+T淋巴细胞在CAF-S1富含的TNBC中的聚集是一致的，并显示了CAF亚群如何参与免疫抑制。
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(High)FOXP3(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.