PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma

High-grade serous ovarian carcinoma (HGSC) remains a disease of 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...

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Bibliographic Details
Published in:	Cancer research (Chicago, Ill.) Vol. 84; no. 22; pp. 3772 - 3787
Main Authors:	Spear, Sarah, Le Saux, Olivia, Mirza, Hasan B, Iyer, Nayana, Tyson, Katie, Grundland Freile, Fabio, Walton, Josephine B, Woodman, Chloe, Jarvis, Sheba, Ennis, Darren P, Aguirre Hernandez, Carmen, Xu, Yuewei, Spiliopoulou, Pavlina, Brenton, James D, Costa-Pereira, Ana P, Cook, David P, Vanderhyden, Barbara C, Keun, Hector C, Triantafyllou, Evangelos, Arnold, James N, McNeish, Iain A
Format:	Journal Article
Language:	English
Published:	United States 15-11-2024
Online Access:	Get full text
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Summary:	High-grade serous ovarian carcinoma (HGSC) remains a disease of 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 derived from peritoneal fluid macrophages and had 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. Furthermore, 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 correlated with activated tumoral PI3K/mTOR signaling and poor overall survival in HGSC patients. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-5472 1538-7445 1538-7445
DOI:	10.1158/0008-5472.CAN-23-3890