Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer

Publication date: Available online 15 February 2018
Source:Cancer Cell
Author(s): Ana Costa, Yann Kieffer, Alix Scholer-Dahirel, Floriane Pelon, Brigitte Bourachot, Melissa Cardon, Philemon Sirven, Ilaria Magagna, Laetitia Fuhrmann, Charles Bernard, Claire Bonneau, Maria Kondratova, Inna Kuperstein, Andrei Zinovyev, Anne-Marie Givel, Maria-Carla Parrini, Vassili Soumelis, Anne Vincent-Salomon, Fatima Mechta-Grigoriou
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.

Graphical abstract

Teaser

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.


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