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

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 con...

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Vydáno v:Nature communications Ročník 15; číslo 1; s. 1312 - 27
Hlavní autoři: Licaj, Monika, Mhaidly, Rana, Kieffer, Yann, Croizer, Hugo, Bonneau, Claire, Meng, Arnaud, Djerroudi, Lounes, Mujangi-Ebeka, Kevin, Hocine, Hocine R., 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
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 12.02.2024
Nature Publishing Group
Nature Portfolio
Témata:
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631/67/1517/1709
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692/4028/67/327
Cancer
Cancer therapies
CD8 antigen
Chemoresistance
Chemotherapy
Clusters
Cytotoxicity
Extracellular matrix
Fibroblasts
Heterogeneity
Humanities and Social Sciences
Immunity
Immunohistochemistry
Life Sciences
Lymphocytes
Lymphocytes T
multidisciplinary
Ovarian cancer
Populations
Science
Science (multidisciplinary)
Signal transduction
Spatial analysis
Stroma
Toxicity
Transcriptomics
Tumors
Yes-associated protein
ISSN:2041-1723, 2041-1723
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Shrnutí: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. An important contribution of cancer associated fibroblasts (CAFs) in regulating chemoresistance has been reported. Here the authors investigate the impact of chemotherapy on CAF subsets in patients with high-grade serous ovarian cancer, suggesting that residual ANTXR1+ myofibroblasts are associated with inhibition of anti-tumor immunity.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-45595-3