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

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Licaj, Monika | Mhaidly, Rana | Kieffer, Yann | Croizer, Hugo | Bonneau, Claire | Meng, Arnaud | Djerroudi, Lounes | Mujangi-Ebeka, Kevin | Hocine, Hocine | Bourachot, Brigitte | Magagna, Ilaria | Leclere, Renaud | Guyonnet, Lea | Bohec, Mylene | Guérin, Coralie | Baulande, Sylvain | Kamal, Maud | Le Tourneau, Christophe | Lecuru, Fabrice | Becette, Véronique | Rouzier, Roman | Vincent-Salomon, Anne | Gentric, Geraldine | Mechta-Grigoriou, Fatima

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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