Hyperinflammatory repolarisation of ovarian cancer patient macrophages by anti-tumour IgE antibody, MOv18, restricts an immunosuppressive macrophage:Treg cell interaction

Gabriel Osborn; Jacobo López-Abente; Rebecca Adams; Roman Laddach; Melanie Grandits; Heather J Bax; Jitesh Chauhan; Giulia Pellizzari; Mano Nakamura; Chara Stavraka; Alicia Chenoweth; Lais C G F Palhares; Theodore Evan; Jessica Hui Cheah Lim; Amanda Gross; Lenny Moise; Shashi Jatiani; Mariangela Figini; Rodolfo Bianchini; Erika Jensen-Jarolim; Sharmistha Ghosh; Ana Montes; Ahmad Sayasneh; Rebecca Kristeleit; Sophia Tsoka; James Spicer; Debra H Josephs; Sophia N Karagiannis

doi:10.1038/s41467-025-57870-y

Hyperinflammatory repolarisation of ovarian cancer patient macrophages by anti-tumour IgE antibody, MOv18, restricts an immunosuppressive macrophage:Treg cell interaction

Gabriel Osborn, Jacobo López-Abente, Rebecca Adams, Roman Laddach, Melanie Grandits, Heather J Bax, Jitesh Chauhan, Giulia Pellizzari, Mano Nakamura, Chara Stavraka, Alicia Chenoweth, Lais C G F Palhares, Theodore Evan, Jessica Hui Cheah Lim, Amanda Gross, Lenny Moise, Shashi Jatiani, Mariangela Figini, Rodolfo Bianchini, Erika Jensen-JarolimSharmistha Ghosh, Ana Montes, Ahmad Sayasneh, Rebecca Kristeleit, Sophia Tsoka, James Spicer, Debra H Josephs, Sophia N Karagiannis

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Abstract

Ovarian cancer is the most lethal gynaecological cancer and treatment options remain limited. In a recent first-in-class Phase I trial, the monoclonal IgE antibody MOv18, specific for the tumour-associated antigen Folate Receptor-α, was well-tolerated and preliminary anti-tumoural activity observed. Pre-clinical studies identified macrophages as mediators of tumour restriction and pro-inflammatory activation by IgE. However, the mechanisms of IgE-mediated modulation of macrophages and downstream tumour immunity in human cancer remain unclear. Here we study macrophages from patients with epithelial ovarian cancers naive to IgE therapy. High-dimensional flow cytometry
and RNA-seq demonstrate immunosuppressive, FcεR-expressing macrophage phenotypes. Ex vivo co-cultures and RNA-seq interaction analyses reveal immunosuppressive associations between patient-derived macrophages and regulatory T (Treg) cells. MOv18 IgE-engaged patient-derived macrophages undergo pro-inflammatory repolarisation ex vivo and display induction of a hyperinflammatory, T cell-stimulatory subset. IgE reverses macrophage-promoted Treg cell induction to increase CD8+ T cell expansion, a signature associated with improved patient prognosis. On-treatment tumours from the MOv18 IgE Phase I trial show evidence of this IgE-driven immune signature, with increased CD68+ and CD3+ cell infiltration. We demonstrate that IgE induces hyperinflammatory repolarised states of patient-derived macrophages to inhibit Treg cell immunosuppression. These processes may collectively promote immune activation in ovarian cancer patients receiving IgE therapy.

Original language	English
Article number	2903
Number of pages	20
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-57870-y https://doi.org/10.1038/s41467-025-57870-y
Publication status	Published - 10 Apr 2025

Keywords

Humans
Female
Ovarian Neoplasms/immunology
T-Lymphocytes, Regulatory/immunology
Macrophages/immunology
Immunoglobulin E/immunology
Carcinoma, Ovarian Epithelial/immunology
Receptors, IgE/metabolism
Folate Receptor 1/immunology
Inflammation/immunology
Middle Aged
CD8-Positive T-Lymphocytes/immunology

UN SDGs

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Osborn et al Nature Communications 2025Final published version, 7.63 MBLicence: CC BY

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Osborn, G., López-Abente, J., Adams, R., Laddach, R., Grandits, M., Bax, H. J., Chauhan, J., Pellizzari, G., Nakamura, M., Stavraka, C., Chenoweth, A., Palhares, L. C. G. F., Evan, T., Lim, J. H. C., Gross, A., Moise, L., Jatiani, S., Figini, M., Bianchini, R., ... Karagiannis, S. N. (2025). Hyperinflammatory repolarisation of ovarian cancer patient macrophages by anti-tumour IgE antibody, MOv18, restricts an immunosuppressive macrophage:Treg cell interaction. Nature Communications, 16(1), Article 2903. https://doi.org/10.1038/s41467-025-57870-y, https://doi.org/10.1038/s41467-025-57870-y

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title = "Hyperinflammatory repolarisation of ovarian cancer patient macrophages by anti-tumour IgE antibody, MOv18, restricts an immunosuppressive macrophage:Treg cell interaction",

abstract = "Ovarian cancer is the most lethal gynaecological cancer and treatment options remain limited. In a recent first-in-class Phase I trial, the monoclonal IgE antibody MOv18, specific for the tumour-associated antigen Folate Receptor-α, was well-tolerated and preliminary anti-tumoural activity observed. Pre-clinical studies identified macrophages as mediators of tumour restriction and pro-inflammatory activation by IgE. However, the mechanisms of IgE-mediated modulation of macrophages and downstream tumour immunity in human cancer remain unclear. Here we study macrophages from patients with epithelial ovarian cancers naive to IgE therapy. High-dimensional flow cytometryand RNA-seq demonstrate immunosuppressive, FcεR-expressing macrophage phenotypes. Ex vivo co-cultures and RNA-seq interaction analyses reveal immunosuppressive associations between patient-derived macrophages and regulatory T (Treg) cells. MOv18 IgE-engaged patient-derived macrophages undergo pro-inflammatory repolarisation ex vivo and display induction of a hyperinflammatory, T cell-stimulatory subset. IgE reverses macrophage-promoted Treg cell induction to increase CD8+ T cell expansion, a signature associated with improved patient prognosis. On-treatment tumours from the MOv18 IgE Phase I trial show evidence of this IgE-driven immune signature, with increased CD68+ and CD3+ cell infiltration. We demonstrate that IgE induces hyperinflammatory repolarised states of patient-derived macrophages to inhibit Treg cell immunosuppression. These processes may collectively promote immune activation in ovarian cancer patients receiving IgE therapy.",

keywords = "Humans, Female, Ovarian Neoplasms/immunology, T-Lymphocytes, Regulatory/immunology, Macrophages/immunology, Immunoglobulin E/immunology, Carcinoma, Ovarian Epithelial/immunology, Receptors, IgE/metabolism, Folate Receptor 1/immunology, Inflammation/immunology, Middle Aged, CD8-Positive T-Lymphocytes/immunology",

author = "Gabriel Osborn and Jacobo L{\'o}pez-Abente and Rebecca Adams and Roman Laddach and Melanie Grandits and Bax, {Heather J} and Jitesh Chauhan and Giulia Pellizzari and Mano Nakamura and Chara Stavraka and Alicia Chenoweth and Palhares, {Lais C G F} and Theodore Evan and Lim, {Jessica Hui Cheah} and Amanda Gross and Lenny Moise and Shashi Jatiani and Mariangela Figini and Rodolfo Bianchini and Erika Jensen-Jarolim and Sharmistha Ghosh and Ana Montes and Ahmad Sayasneh and Rebecca Kristeleit and Sophia Tsoka and James Spicer and Josephs, {Debra H} and Karagiannis, {Sophia N}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

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day = "10",

doi = "10.1038/s41467-025-57870-y",

language = "English",

volume = "16",

journal = "Nature Communications",

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Osborn, G, López-Abente, J, Adams, R , Laddach, R , Grandits, M , Bax, HJ , Chauhan, J , Pellizzari, G , Nakamura, M , Stavraka, C , Chenoweth, A, Palhares, LCGF, Evan, T, Lim, JHC, Gross, A, Moise, L, Jatiani, S, Figini, M, Bianchini, R, Jensen-Jarolim, E, Ghosh, S, Montes, A, Sayasneh, A, Kristeleit, R , Tsoka, S , Spicer, J , Josephs, DH & Karagiannis, SN 2025, 'Hyperinflammatory repolarisation of ovarian cancer patient macrophages by anti-tumour IgE antibody, MOv18, restricts an immunosuppressive macrophage:Treg cell interaction', Nature Communications, vol. 16, no. 1, 2903. https://doi.org/10.1038/s41467-025-57870-y, https://doi.org/10.1038/s41467-025-57870-y

TY - JOUR

T1 - Hyperinflammatory repolarisation of ovarian cancer patient macrophages by anti-tumour IgE antibody, MOv18, restricts an immunosuppressive macrophage:Treg cell interaction

AU - Osborn, Gabriel

AU - López-Abente, Jacobo

AU - Adams, Rebecca

AU - Laddach, Roman

AU - Grandits, Melanie

AU - Bax, Heather J

AU - Chauhan, Jitesh

AU - Pellizzari, Giulia

AU - Nakamura, Mano

AU - Stavraka, Chara

AU - Chenoweth, Alicia

AU - Palhares, Lais C G F

AU - Evan, Theodore

AU - Lim, Jessica Hui Cheah

AU - Gross, Amanda

AU - Moise, Lenny

AU - Jatiani, Shashi

AU - Figini, Mariangela

AU - Bianchini, Rodolfo

AU - Jensen-Jarolim, Erika

AU - Ghosh, Sharmistha

AU - Montes, Ana

AU - Sayasneh, Ahmad

AU - Kristeleit, Rebecca

AU - Tsoka, Sophia

AU - Spicer, James

AU - Josephs, Debra H

AU - Karagiannis, Sophia N

PY - 2025/4/10

Y1 - 2025/4/10

N2 - Ovarian cancer is the most lethal gynaecological cancer and treatment options remain limited. In a recent first-in-class Phase I trial, the monoclonal IgE antibody MOv18, specific for the tumour-associated antigen Folate Receptor-α, was well-tolerated and preliminary anti-tumoural activity observed. Pre-clinical studies identified macrophages as mediators of tumour restriction and pro-inflammatory activation by IgE. However, the mechanisms of IgE-mediated modulation of macrophages and downstream tumour immunity in human cancer remain unclear. Here we study macrophages from patients with epithelial ovarian cancers naive to IgE therapy. High-dimensional flow cytometryand RNA-seq demonstrate immunosuppressive, FcεR-expressing macrophage phenotypes. Ex vivo co-cultures and RNA-seq interaction analyses reveal immunosuppressive associations between patient-derived macrophages and regulatory T (Treg) cells. MOv18 IgE-engaged patient-derived macrophages undergo pro-inflammatory repolarisation ex vivo and display induction of a hyperinflammatory, T cell-stimulatory subset. IgE reverses macrophage-promoted Treg cell induction to increase CD8+ T cell expansion, a signature associated with improved patient prognosis. On-treatment tumours from the MOv18 IgE Phase I trial show evidence of this IgE-driven immune signature, with increased CD68+ and CD3+ cell infiltration. We demonstrate that IgE induces hyperinflammatory repolarised states of patient-derived macrophages to inhibit Treg cell immunosuppression. These processes may collectively promote immune activation in ovarian cancer patients receiving IgE therapy.

AB - Ovarian cancer is the most lethal gynaecological cancer and treatment options remain limited. In a recent first-in-class Phase I trial, the monoclonal IgE antibody MOv18, specific for the tumour-associated antigen Folate Receptor-α, was well-tolerated and preliminary anti-tumoural activity observed. Pre-clinical studies identified macrophages as mediators of tumour restriction and pro-inflammatory activation by IgE. However, the mechanisms of IgE-mediated modulation of macrophages and downstream tumour immunity in human cancer remain unclear. Here we study macrophages from patients with epithelial ovarian cancers naive to IgE therapy. High-dimensional flow cytometryand RNA-seq demonstrate immunosuppressive, FcεR-expressing macrophage phenotypes. Ex vivo co-cultures and RNA-seq interaction analyses reveal immunosuppressive associations between patient-derived macrophages and regulatory T (Treg) cells. MOv18 IgE-engaged patient-derived macrophages undergo pro-inflammatory repolarisation ex vivo and display induction of a hyperinflammatory, T cell-stimulatory subset. IgE reverses macrophage-promoted Treg cell induction to increase CD8+ T cell expansion, a signature associated with improved patient prognosis. On-treatment tumours from the MOv18 IgE Phase I trial show evidence of this IgE-driven immune signature, with increased CD68+ and CD3+ cell infiltration. We demonstrate that IgE induces hyperinflammatory repolarised states of patient-derived macrophages to inhibit Treg cell immunosuppression. These processes may collectively promote immune activation in ovarian cancer patients receiving IgE therapy.

KW - Humans

KW - Female

KW - Ovarian Neoplasms/immunology

KW - T-Lymphocytes, Regulatory/immunology

KW - Macrophages/immunology

KW - Immunoglobulin E/immunology

KW - Carcinoma, Ovarian Epithelial/immunology

KW - Receptors, IgE/metabolism

KW - Folate Receptor 1/immunology

KW - Inflammation/immunology

KW - Middle Aged

KW - CD8-Positive T-Lymphocytes/immunology

UR - http://www.scopus.com/inward/record.url?scp=105002965076&partnerID=8YFLogxK

U2 - 10.1038/s41467-025-57870-y

DO - 10.1038/s41467-025-57870-y

M3 - Article

C2 - 40210642

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2903

ER -

Hyperinflammatory repolarisation of ovarian cancer patient macrophages by anti-tumour IgE antibody, MOv18, restricts an immunosuppressive macrophage:Treg cell interaction

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Keywords

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