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Published on: May 20, 2014
PTEN Loss Shapes Macrophage Dynamics in High-Grade Serous Ovarian Carcinoma
Sarah Spear1, Olivia Le Saux1,2, Hasan B Mirza1
1Ovarian Cancer Action Research Centre, Department of Surgery & Cancer, Imperial College London; London, United Kingdom.
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.
Insights
High-grade serous ovarian carcinoma (HGSC) with PTEN loss features tumor-promoting macrophages. Targeting heme oxygenase-1 (HMOX1) in these macrophages may offer a new therapeutic strategy for HGSC patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- High-grade serous ovarian carcinoma (HGSC) has a poor prognosis and is resistant to immune checkpoint inhibitors.
- PI3K pathway alterations, including PTEN loss, are frequent in HGSC but therapeutic targeting has been unsuccessful.
- Aberrant PI3K pathway activation may influence the HGSC immune microenvironment, presenting a potential therapeutic vulnerability.
Purpose of the Study:
- To investigate the role of PI3K pathway activation in shaping the HGSC immune microenvironment.
- To identify specific macrophage populations associated with PTEN-deficient HGSC.
- To explore targeting heme oxygenase-1 (HMOX1) as a therapeutic strategy for HGSC.
Main Methods:
- Single-cell RNA sequencing and flow cytometry in murine models of Pten-null HGSC.
- Analysis of gene expression in tumor cells and tumor-infiltrating macrophages.
- In vivo experiments involving targeting peritoneal macrophages and direct HMOX1 inhibition.
- Correlation analysis of macrophage populations with clinical data from human HGSC patients.
Main Results:
- Pten-null HGSC models exhibit unique resident peritoneal macrophages (HMOX1hi macrophages) derived from peritoneal fluid macrophages.
- Targeting these macrophages or inhibiting HMOX1 reduced tumor growth and extended survival in vivo.
- IL33 in Pten-null tumor cells was identified as a potential driver for HMOX1hi macrophage recruitment.
- Human HGSC tumors showed enrichment of HMOX1hi macrophages, correlated with activated PI3K/mTOR signaling and poor survival.
Conclusions:
- HMOX1hi macrophages are a hallmark of PTEN-deficient HGSC and contribute to tumor progression.
- Targeting HMOX1hi macrophages represents a promising therapeutic avenue for improving outcomes in HGSC.
- The presence of HMOX1hi macrophages is inversely correlated with adaptive immune responses in HGSC tumors.
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