成纤维细胞异质性和人乳腺癌中的免疫抑制微环境。

Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer.

机构信息

Institut Curie, Stress and Cancer Laboratory, Equipe labelisée Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France.

Institut Curie, Stress and Cancer Laboratory, Equipe labelisée Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France; Institut Curie, Integrative Biology of Human Dendritic Cells and T Cells Laboratory, PSL Research University, Inserm, U932, 26, rue d'Ulm, 75005 Paris, France.

出版信息

Cancer Cell. 2018 Mar 12;33(3):463-479.e10. doi: 10.1016/j.ccell.2018.01.011. Epub 2018 Feb 15.

DOI:10.1016/j.ccell.2018.01.011

PMID:29455927

Abstract

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 CD4CD25 T lymphocytes and retains them by OX40L, PD-L2, and JAM2. Moreover, CAF-S1 increases T lymphocyte survival and promotes their differentiation into CD25FOXP3, 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.

摘要

癌相关成纤维细胞（CAF）是肿瘤微环境中的关键参与者。在这里，我们描述了乳腺癌中具有不同特性和激活水平的四种 CAF 亚群。两种肌成纤维细胞亚群（CAF-S1、CAF-S4）在三阴性乳腺癌（TNBC）中差异积累。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 吸引 CD4CD25 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 淋巴细胞的存活并促进其分化为 CD25FOXP3。最后，与 CAF-S4 相比，CAF-S1 增强了调节性 T 细胞抑制 T 效应细胞增殖的能力。这些数据与 CAF-S1 富集的 TNBC 中 FOXP3+T 淋巴细胞的积累一致，并显示了 CAF 亚群如何有助于免疫抑制。