<i>PTEN</i> Loss Shapes Macrophage Dynamics in High-Grade Serous Ovarian Carcinoma

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.

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Publication Details

Journal
Cancer Research
Published
2024-08-26
DOI
https://doi.org/10.1158/0008-5472.can-23-3890
Citations
7
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
1.68

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article

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

Carmen Aguirre Hernandez, Sheba Jarvis, Hasan Mirza, Ana P. Costa‐Pereira et al.
7 citations
Cancer Research
Immune Cell Function and Interaction
1.68
article

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

Carmen Aguirre Hernandez, Sheba Jarvis, Hasan Mirza, Ana P. Costa‐Pereira, Pavlina Spiliopoulou, Josephine Walton, Barbara C. Vanderhyden, Nayana Iyer, Hector C. Keun, James D. Brenton, James N. Arnold, Fabio Grundland-Freile, Sarah Spear, Olivia Le Saux, Evangelos Triantafyllou, David P. Cook, Yuewei Xu, Iain A. McNeish, Darren Ennis, Chloé Woodman, Katie Tyson
article en
7 citations

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.

Cancer ResearchVol. 84(22)
University of Ottawa (CA), Queen Mary University of London (GB), King's College London (GB), University of Cambridge (GB), Ottawa Hospital (CA), London Cancer (GB), Ovarian Cancer Action (GB), Bridge University (SS), Centre Léon Bérard (FR), Ottawa Hospital Research Institute (CA), Imperial College London (GB), University of Glasgow (GB)
Cancer Research Institute, Cancer Research UK, National Institute for Health and Care Research, Ovarian Cancer Action, Imperial College London, Ligue Contre le Cancer, China Scholarship Council, Imperial Experimental Cancer Medicine Centre, Biotechnology and Biological Sciences Research Council, NIHR Imperial Biomedical Research Centre
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Openalex Percentile: Top 16%
Immune Cell Function and Interaction
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