Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer

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Croizer, Hugo | Mhaidly, Rana | Kieffer, Yann | Gentric, Geraldine | Djerroudi, Lounes | Leclere, Renaud | Pelon, Floriane | Robley, Catherine | Bohec, Mylene | Meng, Arnaud | Meseure, Didier | Romano, Emanuela | Baulande, Sylvain | Peltier, Agathe | Vincent-Salomon, Anne | Mechta-Grigoriou, Fatima

Edité par CCSD ; Nature Publishing Group -

International audience. Abstract Although heterogeneity of FAP+ Cancer-Associated Fibroblasts (CAF) has been described in breast cancer, their plasticity and spatial distribution remain poorly understood. Here, we analyze trajectory inference, deconvolute spatial transcriptomics at single-cell level and perform functional assays to generate a high-resolution integrated map of breast cancer (BC), with a focus on inflammatory and myofibroblastic (iCAF/myCAF) FAP+ CAF clusters. We identify 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are differentially localized within tumors. Consistent with their spatial organization, cancer cells drive the transition of detoxification-associated iCAF (Detox-iCAF) towards immunosuppressive extracellular matrix (ECM)-producing myCAF (ECM-myCAF) via a DPP4- and YAP-dependent mechanism. In turn, ECM-myCAF polarize TREM2+ macrophages, regulatory NK and T cells to induce immunosuppressive EcoCellTypes, while Detox-iCAF are associated with FOLR2+ macrophages in an immuno-protective EcoCellType. FAP+ CAF subpopulations accumulate differently according to the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation.

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