期刊
CANCER DISCOVERY
卷 10, 期 9, 页码 1330-1351出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-1384
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资金
- Institut National du Cancer, INCa [INCa-DGOS-9963, INCa-11692]
- SIRIC [INCa-DGOS-4654]
- Medical Research Foundation (FRM)
- Foundation ARC (AAP SIGN'IT 2019)
- foundation Chercher et Trouver
- Agence Nationale de la recherche [ANR-19-P3IA-0001]
- France Genomique Consortium [ANR-10-INBS-09-08]
- Ligue Nationale Contre le Cancer (Labelisation)
- Inserm [PC201317]
- Institut Curie (Incentive and Cooperative Program Tumor Micro-environment PIC TME/T-MEGA, PIC3i CAFi)
- Bristol-Myers Squibb Foundation
- ICGex [ANR-10-EQPX-03]
- INCa (STROMAE) [INCa-DGOS-9963]
- INCa (CaLYS ) [INCa-11692]
- INCa [INCa-DGOS-Inserm-12554]
A subset of cancer-associated fibroblasts (FAP(+)/CAF-S1) mediates immunosup- pression 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 TGF beta 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/TGF beta-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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