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  • Species: human
  • Number of cells: 18296
  • Number of downloads: 115
  • Study size: 402MB
  • Uploaded at: Nov 12, 2020

CAFcancer associated fibroblastbreast cancer

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

Yann Kieffer, Hocine R. Hocine, Géraldine Gentric, Floriane Pelon, Charles Bernard, Brigitte Bourachot, Sonia Lameiras, Luca Albergante, Claire Bonneau, Alice Guyard, Karin Tarte, Andrei Zinovyev, Sylvain Baulande, Gerard Zalcman, Anne Vincent-Salomon, Fatima Mechta-Grigoriou

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. Significance: Our work provides a significant advance in characterizing and understanding FAP+ CAF in cancer. We reached a high resolution at single-cell level, which enabled us to identify specific clusters associated with immunosuppression and immunotherapy resistance. Identification of cluster-specific signatures paves the way for therapeutic options in combination with immunotherapies.

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