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Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer

Kieffer, Yann and Hocine, Hocine R and Gentric, Geraldine and Pelon, Floriane and Bernard, Charles and Bourachot, Brigitte and Lameiras, Sonia and Albergante, Luca and Bonneau, Claire and Guyard, Alice and others

A subset of cancer-associated fibroblasts (FAP+/CAF-S1) mediates immunosuppression in breast cancers, but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19,000 single CAF-S1 fibroblasts from breast cancer. We validate the five most abundant clusters by flow cytometry and in silico analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extracellular matrix proteins and TGFβ signaling, respectively, are indicative of primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 and CTLA4 protein levels in regulatory T lymphocytes (Tregs), which, in turn, increases CAF-S1 cluster 3/TGFβ-myCAF cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance.

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Species: human
Number of cells: 18296
Number of downloads: 87
Study size: 764MB
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cancer associated fibroblast 
breast cancer