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Immunotherapy that improves response to chemotherapy in high-grade serous ovarian cancer

Author

Listed:
  • Samar Elorbany

    (Charterhouse Square)

  • Chiara Berlato

    (Charterhouse Square)

  • Larissa S. Carnevalli

    (AstraZeneca)

  • Eleni Maniati

    (Charterhouse Square)

  • Simon T. Barry

    (AstraZeneca)

  • Jun Wang

    (Charterhouse Square)

  • Ranjit Manchanda

    (Queen Mary University of London
    Barts Health NHS Trust)

  • Julia Kzhyshkowska

    (Heidelberg University
    German Red Cross Blood Service Baden-Württemberg-Hessen)

  • Frances Balkwill

    (Charterhouse Square)

Abstract

Single-cell RNA sequencing (scRNAseq) of tumour-infiltrating immune cells in high-grade serous ovarian cancer (HGSOC) omental biopsies reveals potential targets that could enhance response to neo-adjuvant chemotherapy (NACT). Analysis of 64,097 cells identifies NACT-induced overexpression of stabilin-1 (clever-1) on macrophages and FOXP3 in Tregs that is confirmed at the protein level. STAB1 inhibition in vitro induces anti-tumour macrophages. FOXP3 anti-sense oligonucleotide (FOXP3-ASO), repolarises Tregs to an effector T cell phenotype. ScRNAseq on 69,781 cells from an HGSOC syngeneic mouse model recapitulates the patients’ data. Combining chemotherapy with anti-stabilin1 antibody and/or Foxp3-ASO significantly increases survival of mice with established peritoneal disease in two HGSOC syngeneic models and progression-free survival in a third model. Long-term survivors (300 days + ) are resistant to tumour rechallenge. Anti-stabilin1 antibody enriches the tumours with CXCL9+ macrophages and Foxp3-ASO increases TBET cell infiltration. Our results suggest that targeting these molecules in immune cells may improve chemotherapy response in patients.

Suggested Citation

  • Samar Elorbany & Chiara Berlato & Larissa S. Carnevalli & Eleni Maniati & Simon T. Barry & Jun Wang & Ranjit Manchanda & Julia Kzhyshkowska & Frances Balkwill, 2024. "Immunotherapy that improves response to chemotherapy in high-grade serous ovarian cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54295-x
    DOI: 10.1038/s41467-024-54295-x
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