Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

Abstract

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.

People
Spear, Sarah
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Le Saux, Olivia
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Mirza, Hasan B.
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Iyer, Nayana
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Tyson, Katie
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Grundland Freile, Fabio
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Walton, Josephine B.
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Woodman, Chloe
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Jarvis, Sheba
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Ennis, Darren P.
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Aguirre Hernandez, Carmen
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Xu, Yuewei
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Spiliopoulou, Pavlina
Author

Cartwright, Douglas and Kidd, Andrew C. and Ansel, Sonam and Ascierto, Maria Libera and Spiliopoulou, Pavlina (2025) Oncogenic signalling pathways in cancer immunotherapy: leader or follower in this delicate dance? International Journal of Molecular Sciences, 26 (9): 4393. ISSN 1661-6596

Genta, S. and Araujo, D.V. and Hueniken, K. and Pipinikas, C. and Ventura, R. and Rojas, P. and Jones, G. and Butler, M.O. and Saibil, S.D. and Yu, C. and Easson, A. and Covelli, A. and Sauder, M.B. and Fournier, C. and Saeed Kamil, Z. and Rogalla, P. and Arteaga, D.P. and Vornicova, O. and Spiliopoulou, Pavlina and Muniz, T.P. and Siu, L.L. and Spreafico, A. (2024) Bespoke ctDNA for longitudinal detection of molecular residual disease in high-risk melanoma patients. ESMO Open, 9 (11): 103978. ISSN 2059-7029

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Brenton, James D.
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

Neilson, Lisa J. and Cartwright, Douglas and Risteli, Maija and Jokinen, Elina M. and McGarry, Lynn and Sandvik, Toni and Nikolatou, Konstantina and Hodge, Kelly and Atkinson, Samuel and Vias, Maria and Kay, Emily J. and Brenton, James D. and Carlin, Leo M. and Bryant, David M. and Salo, Tuula and Zanivan, Sara (2023) Omentum-derived matrix enables the study of metastatic ovarian cancer and stromal cell functions in a physiologically relevant environment. Matrix Biology Plus, 19-20: 100136. ISSN 2590-0285

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Costa-Pereira, Ana P.
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Cook, David P.
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Vanderhyden, Barbara C.
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Keun, Hector C.
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Triantafyllou, Evangelos
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Arnold, James N.
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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McNeish, Iain A.
Author

Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A. (2024) PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma. Cancer Research. ISSN 0008-5472 (In Press)

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Title:
PTEN loss shapes macrophage dynamics in high grade serous ovarian carcinoma
Creators:
Spear, Sarah and Le Saux, Olivia and Mirza, Hasan B. and Iyer, Nayana and Tyson, Katie and Grundland Freile, Fabio and Walton, Josephine B. and Woodman, Chloe and Jarvis, Sheba and Ennis, Darren P. and Aguirre Hernandez, Carmen and Xu, Yuewei and Spiliopoulou, Pavlina and Brenton, James D. and Costa-Pereira, Ana P. and Cook, David P. and Vanderhyden, Barbara C. and Keun, Hector C. and Triantafyllou, Evangelos and Arnold, James N. and McNeish, Iain A.
Identification Number:
10.1158/0008-5472.can-23-3890
Date:
26 August 2024
Divisions:
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher:
American Association for Cancer Research
Additional Information:
This work was funded by Ovarian Cancer Action (references P72914, P76567 and PSF687) and Cancer Research UK (grant reference C608/A15973). JNA is supported by grants from Cancer Research UK (DCRPGF\100009) and Cancer Research Institute / Wade F.B. Thompson CLIP grant (CRI3645). Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre and the Imperial Experimental Cancer Medicine Centre, but this was not used to support mouse experiments. IMcN also receives funding as an NIHR Senior Investigator. OLS is a recipient of grants from La Ligue contre le Cancer, La Fondation Nuovo-Soldati, and Canceropole Lyon Auvergne Rhone-Alpes. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. YX is funded by a joint PhD scholarship between Imperial College London and China Scholarship Council (201808060050). NI is funded by Imperial College London President’s PhD Scholarship. JW was funded by a CRUK PhD studentship.
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https://pub.demo35.eprints-hosting.org/id/eprint/177
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Date Deposited:
11 Jun 2025 16:35
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