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Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

Author

Listed:
  • I.-M. Launonen

    (University of Helsinki)

  • N. Lyytikäinen

    (University of Helsinki)

  • J. Casado

    (University of Helsinki)

  • E. A. Anttila

    (University of Helsinki)

  • A. Szabó

    (University of Helsinki)

  • U.-M. Haltia

    (University of Helsinki
    Helsinki University Hospital)

  • C. A. Jacobson

    (Harvard Medical School)

  • J. R. Lin

    (Harvard Medical School)

  • Z. Maliga

    (Harvard Medical School)

  • B. E. Howitt

    (Stanford University School of Medicine)

  • K. C. Strickland

    (Duke University Medical Center)

  • S. Santagata

    (Harvard Medical School
    Brigham and Women’s Hospital
    Harvard Medical School)

  • K. Elias

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • A. D. D’Andrea

    (Harvard Medical School)

  • P. A. Konstantinopoulos

    (Harvard Medical School)

  • P. K. Sorger

    (Harvard Medical School
    Harvard Medical School)

  • A. Färkkilä

    (University of Helsinki
    Helsinki University Hospital
    Harvard Medical School
    Harvard Medical School)

Abstract

The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generate spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes. We identify a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we report a prognostic role of a proliferative tumor-cell subpopulation, which associates with enhanced spatial tumor-immune interactions by CD8+ and CD4 + T-cells in the BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the potential to improve immunotherapeutic strategies and patient stratification in HGSC.

Suggested Citation

  • I.-M. Launonen & N. Lyytikäinen & J. Casado & E. A. Anttila & A. Szabó & U.-M. Haltia & C. A. Jacobson & J. R. Lin & Z. Maliga & B. E. Howitt & K. C. Strickland & S. Santagata & K. Elias & A. D. D’And, 2022. "Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28389-3
    DOI: 10.1038/s41467-022-28389-3
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    References listed on IDEAS

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    1. Hiro Sato & Atsuko Niimi & Takaaki Yasuhara & Tiara Bunga Mayang Permata & Yoshihiko Hagiwara & Mayu Isono & Endang Nuryadi & Ryota Sekine & Takahiro Oike & Sangeeta Kakoti & Yuya Yoshimoto & Kathryn , 2017. "DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    2. Mélanie Desbois & Akshata R. Udyavar & Lisa Ryner & Cleopatra Kozlowski & Yinghui Guan & Milena Dürrbaum & Shan Lu & Jean-Philippe Fortin & Hartmut Koeppen & James Ziai & Ching-Wei Chang & Shilpa Keer, 2020. "Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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