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

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, a team led by researchers at the Institut Curie identify 8 CAF-S1 clusters by analyzing more than 19,000 single CAF-S1 fibroblasts from breast cancer. They 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, this study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance.

This work provides a significant advance in characterizing and understanding FAP⁺ CAF in cancer. The researchers reached a high resolution at single-cell level, which enabled them 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.