Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway

Monika Licaj, Rana Mhaidly, Yann Kieffer, Hugo Croizer, Claire Bonneau, Arnaud Meng, Lounes Djerroudi, Kevin Mujangi-Ebeka, Hocine R. Hocine, Brigitte Bourachot, Ilaria Magagna, Renaud Leclere, Lea Guyonnet, Mylene Bohec, Coralie Guérin, Sylvain Baulande, Maud Kamal, Christophe Tourneau, Fabrice Lecuru, Véronique Becette, Roman Rouzier, Anne Vincent-Salomon, Geraldine Gentric () and Fatima Mechta-Grigoriou ()
Additional contact information
Monika Licaj: PSL Research University
Rana Mhaidly: PSL Research University
Yann Kieffer: PSL Research University
Hugo Croizer: PSL Research University
Claire Bonneau: PSL Research University
Arnaud Meng: PSL Research University
Lounes Djerroudi: PSL Research University
Kevin Mujangi-Ebeka: PSL Research University
Hocine R. Hocine: PSL Research University
Brigitte Bourachot: PSL Research University
Ilaria Magagna: PSL Research University
Renaud Leclere: Institut Curie Hospital Group
Lea Guyonnet: Cytometry platform, PSL University, Institut Curie
Mylene Bohec: PSL University, Institut Curie
Coralie Guérin: Cytometry platform, PSL University, Institut Curie
Sylvain Baulande: PSL University, Institut Curie
Maud Kamal: Institut Curie Hospital Group
Christophe Tourneau: Institut Curie Hospital Group
Fabrice Lecuru: Paris Cité University
Véronique Becette: Institut Curie Hospital Group
Roman Rouzier: Institut Curie Hospital Group
Anne Vincent-Salomon: Institut Curie Hospital Group
Geraldine Gentric: PSL Research University
Fatima Mechta-Grigoriou: PSL Research University

Nature Communications, 2024, vol. 15, issue 1, 1-27

Abstract: Abstract Although cancer-associated fibroblast (CAF) heterogeneity is well-established, the impact of chemotherapy on CAF populations remains poorly understood. Here we address this question in high-grade serous ovarian cancer (HGSOC), in which we previously identified 4 CAF populations. While the global content in stroma increases in HGSOC after chemotherapy, the proportion of FAP+ CAF (also called CAF-S1) decreases. Still, maintenance of high residual CAF-S1 content after chemotherapy is associated with reduced CD8+ T lymphocyte density and poor patient prognosis, emphasizing the importance of CAF-S1 reduction upon treatment. Single cell analysis, spatial transcriptomics and immunohistochemistry reveal that the content in the ECM-producing ANTXR1+ CAF-S1 cluster (ECM-myCAF) is the most affected by chemotherapy. Moreover, functional assays demonstrate that ECM-myCAF isolated from HGSOC reduce CD8+ T-cell cytotoxicity through a Yes Associated Protein 1 (YAP1)-dependent mechanism. Thus, efficient inhibition after treatment of YAP1-signaling pathway in the ECM-myCAF cluster could enhance CD8+ T-cell cytotoxicity. Altogether, these data pave the way for therapy targeting YAP1 in ECM-myCAF in HGSOC.

Date: 2024
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DOI: 10.1038/s41467-024-45595-3

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