Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer.

By Y. Kieffer, H. Hocine, Géraldine Gentric, Floriane Pelon, Charles Bernard, B. Bourachot, S. Lameiras, Luca Albergante, C. Bonneau, A. Guyard and 6 more. Cancer Discovery, 2020

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A subset of Cancer-Associated Fibroblasts (FAP+/CAF-S1) mediates immunosuppression in breast cancers (BC), but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19000 single CAF-S1 fibroblasts from BC. We validate the 5 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 extra-cellular matrix proteins and TGFB signaling respectively, are indicative of primary resistance to immunotherapies. Cluster 0/ecm-myCAF up-regulates PD-1 and CTLA-4 protein levels in regulatory T lymphocytes (Tregs), which in turn increases CAF-S1 cluster 3/TGFB-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.

Subfields: Biomedical Engineering, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/d0cdf7f9f28a055ed86bd25ae111ef8fcc0259b1