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

Yann Kieffer (1) , Hocine Rachid Hocine (1) , Géraldine Gentric (1) , Floriane Pelon (1) , Charles Bernard (1) , Brigitte Bourachot (1) , Sonia Lameiras (1, 2) , Luca Albergante (3) , Claire Bonneau (1) , Alice Guyard (4) , Karin Tarte (5) , Andrei Zinovyev (1) , Sylvain Baulande (1) , Gérard Zalcman (4) , Anne Vincent-Salomon (1) , Fatima Mechta-Grigoriou (1)

1 Institut Curie [Paris]
2 Genomics of Excellence (ICGex) Platform
3 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
4 CIC - CHU Bichat
5 MICMAC - Microenvironment, Cell Differentiation, Immunology and Cancer

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.

Domaines: Cancer

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, 2020, 10 (9), pp.1330-1351. ⟨10.1158/2159-8290.CD-19-1384⟩. ⟨hal-02890211⟩