PTEN Loss Shapes Macrophage Dynamics in High-Grade Serous Ovarian Carcinoma.

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  • Additional Information
    • Source:
      Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
    • Publication Information:
      Publication: Baltimore, Md. : American Association for Cancer Research
      Original Publication: Chicago [etc.]
    • Subject Terms:
      PTEN Phosphohydrolase*/genetics ; PTEN Phosphohydrolase*/metabolism ; Ovarian Neoplasms*/pathology ; Ovarian Neoplasms*/immunology ; Ovarian Neoplasms*/genetics ; Ovarian Neoplasms*/metabolism ; Cystadenocarcinoma, Serous*/pathology ; Cystadenocarcinoma, Serous*/genetics ; Cystadenocarcinoma, Serous*/immunology ; Cystadenocarcinoma, Serous*/metabolism ; Tumor Microenvironment*/immunology ; Heme Oxygenase-1*/metabolism ; Heme Oxygenase-1*/genetics; Female ; Animals ; Humans ; Mice ; Macrophages/immunology ; Macrophages/metabolism ; Macrophages/pathology ; Cell Line, Tumor ; Mice, Inbred C57BL
    • Abstract:
      High-grade serous ovarian carcinoma (HGSC) remains a disease with poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity. Single-cell RNA sequencing identified populations of resident macrophages specific to Pten-null omental tumors in murine models, which were confirmed by flow cytometry. These macrophages were derived from peritoneal fluid macrophages and exhibited a unique gene expression program, marked by high expression of the enzyme heme oxygenase-1 (HMOX1). Targeting resident peritoneal macrophages prevented the appearance of HMOX1hi macrophages and reduced tumor growth. In addition, direct inhibition of HMOX1 extended survival in vivo. RNA sequencing identified IL33 in Pten-null tumor cells as a likely candidate driver, leading to the appearance of HMOX1hi macrophages. Human HGSC tumors also contained HMOX1hi macrophages with a corresponding gene expression program. Moreover, the presence of these macrophages was correlated with activated tumoral PI3K/mTOR signaling and poor overall survival in patients with HGSC. In contrast, tumors with low numbers of HMOX1hi macrophages were marked by increased adaptive immune response gene expression. These data suggest targeting HMOX1hi macrophages as a potential therapeutic strategy for treating poor prognosis HGSC. Significance: Macrophages with elevated HMOX1 expression are enriched in PTEN-deficient high-grade serous ovarian carcinoma, promote tumor growth, and represent a potential therapeutic target.
      (©2024 The Authors; Published by the American Association for Cancer Research.)
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    • Grant Information:
      15973 United Kingdom CRUK_ Cancer Research UK; C608/A15973 Cancer Research UK (CRUK); DCRPGF\100009 Cancer Research UK (CRUK); PSF687 Ovarian Cancer Action; CRI3645 Cancer Research Institute (CRI); NIHR Imperial Biomedical Research Centre (BRC); Imperial Experimental Cancer Medicine Centre (ECMC); La Ligue contre le Cancer; Canceropole Lyon Auvergne Rhone-Alpes; La Fondation Nuovo-Soldati
    • Accession Number:
      EC 3.1.3.67 (PTEN Phosphohydrolase)
      EC 3.1.3.67 (PTEN protein, human)
      EC 1.14.14.18 (Heme Oxygenase-1)
      EC 3.1.3.67 (Pten protein, mouse)
      EC 1.14.14.18 (HMOX1 protein, human)
    • Publication Date:
      Date Created: 20240826 Date Completed: 20241115 Latest Revision: 20241116
    • Publication Date:
      20241116
    • Accession Number:
      PMC7616669
    • Accession Number:
      10.1158/0008-5472.CAN-23-3890
    • Accession Number:
      39186679