Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer

• Published in: Cancer cell Vol. 33; no. 3; pp. 463 - 479.e10
• Main Authors: Costa, Ana, Kieffer, Yann, Scholer-Dahirel, Alix, Pelon, Floriane, Bourachot, Brigitte, Cardon, Melissa, Sirven, Philemon, Magagna, Ilaria, Fuhrmann, Laetitia, Bernard, Charles, Bonneau, Claire, Kondratova, Maria, Kuperstein, Inna, Zinovyev, Andrei, Givel, Anne-Marie, Parrini, Maria-Carla, Soumelis, Vassili, Vincent-Salomon, Anne, Mechta-Grigoriou, Fatima
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-03-2018; Elsevier
• Subjects: breast cancers; Breast Neoplasms - immunology; CAF; Cancer; Cell Differentiation - physiology; Cell Proliferation - physiology; fibroblasts; Fibroblasts - immunology; Forkhead Transcription Factors - immunology; FOXP3; heterogeneity; Humans; Immune Tolerance - immunology; Life Sciences; Lymphocyte Activation - physiology; Lymphocytes, Tumor-Infiltrating - immunology; regulatory T cell; stroma; T lymphocytes; T-Lymphocytes, Regulatory - immunology; Treg; triple-negative; Tumor Microenvironment - immunology; T lymphocytes; fibroblasts; stroma; Treg; CAF; FOXP3; triple-negative; heterogeneity; breast cancers; regulatory T cell; regulatory T cell
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2018.01.011

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 CD25HighFOXP3High, 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.
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•Four CAF subsets identified in breast cancer accumulate differently in BC subtypes•CAF-S1 subset is associated with an immunosuppressive microenvironment•CAF-S1 cells attract and retain CD4+CD25+ T cells through OX40L, PD-L2, and JAM2•CAF-S1 cells increase CD25+FOXP3+ T lymphocytes, through B7H3, DPP4, and CD73
Costa et al. identify four subsets of carcinoma-associated fibroblasts (CAF) in breast cancer. CAF-S1 promotes an immunosuppressive microenvironment by recruiting CD4+CD25+ T cells, via secreting CXCL12, and promoting their differentiation to Tregs and survival, via expressing T cell interacting proteins.