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 Leclère, Léa Guyonnet, Mylène Bohec, Coralie L. Guérin, Sylvain Baulande, Maud Kamal, Christophe Le Tourneau, Fabrice Lécuru, Véronique Becette, Roman Rouzier, Anne Vincent‐Salomon, Géraldine Gentric, Fatima Mechta‐Grigoriou
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.