Investigating carcinoma-associated fibroblast (CAF) heterogeneity in human breast cancer, Costa et al. identified four distinct subsets which show different accumulation patterns in normal versus tumor tissue, as well as between different breast cancer subtypes. The CAF-S1 subset was found to promote an immunosuppressive microenvironment by upregulating CXCL12 to attract CD4+CD25+ T cells; OX40L, PD-L2, and JAM2 to retain them; and B7H3, DPP4, and CD73 to promote their activation and differentiation into Tregs.

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.

Author Info: (1) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830

Author Info: (1) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. (2) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. (3) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee 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. (4) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. (5) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. (6) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. (7) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee 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. (8) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. (9) Department of Pathology, Institut Curie Hospital Group, 26, rue d'Ulm, 75248 Paris, France. (10) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. (11) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. (12) Institut Curie, PSL Research University, Inserm, U900, Mines Paris Tech, Paris 75005, France. (13) Institut Curie, PSL Research University, Inserm, U900, Mines Paris Tech, Paris 75005, France. (14) Institut Curie, PSL Research University, Inserm, U900, Mines Paris Tech, Paris 75005, France. (15) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. (16) Analysis of Transduction Pathway, Institut Curie, Inserm, U830, PSL Research University, 26 rue d'Ulm, Paris 75005, France. (17) Institut Curie, Integrative Biology of Human Dendritic Cells and T Cells Laboratory, PSL Research University, Inserm, U932, 26, rue d'Ulm, 75005 Paris, France. (18) Department of Pathology, Institut Curie Hospital Group, 26, rue d'Ulm, 75248 Paris, France. (19) Institut Curie, Stress and Cancer Laboratory, Equipe labelisee Ligue Nationale Contre le Cancer, PSL Research University, 26, rue d'Ulm, 75005 Paris, France; Inserm, U830, Paris 75005, France. Electronic address: fatima.mechta-grigoriou@curie.fr.

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