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

Author

Listed:
  • Monika Licaj

    (PSL Research University
    Inserm, U830)

  • Rana Mhaidly

    (PSL Research University
    Inserm, U830)

  • Yann Kieffer

    (PSL Research University
    Inserm, U830)

  • Hugo Croizer

    (PSL Research University
    Inserm, U830)

  • Claire Bonneau

    (PSL Research University
    Inserm, U830
    Institut Curie Hospital Group)

  • Arnaud Meng

    (PSL Research University
    Inserm, U830)

  • Lounes Djerroudi

    (PSL Research University
    Inserm, U830
    Institut Curie Hospital Group)

  • Kevin Mujangi-Ebeka

    (PSL Research University
    Inserm, U830)

  • Hocine R. Hocine

    (PSL Research University
    Inserm, U830)

  • Brigitte Bourachot

    (PSL Research University
    Inserm, U830)

  • Ilaria Magagna

    (PSL Research University
    Inserm, U830)

  • 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
    Paris-Saclay University, Institut Curie)

  • 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
    Inserm, U830)

  • Fatima Mechta-Grigoriou

    (PSL Research University
    Inserm, U830)

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.

Suggested Citation

  • 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 Lecl, 2024. "Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45595-3
    DOI: 10.1038/s41467-024-45595-3
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