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

Abstract : 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.
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https://hal.archives-ouvertes.fr/hal-02890211
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Submitted on : Thursday, July 9, 2020 - 3:56:15 PM
Last modification on : Wednesday, January 20, 2021 - 9:57:20 AM
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Yann Kieffer, Hocine Rachid Hocine, Géraldine Gentric, Floriane Pelon, Charles Bernard, et al.. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discovery, American Association for Cancer Research, 2020, 10 (9), pp.1330-1351. ⟨10.1158/2159-8290.CD-19-1384⟩. ⟨hal-02890211⟩

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