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.