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

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Title (eng)

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

Author

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

University of Veterinary Medicine Vienna

Sharmistha Ghosh

Ana Montes

Ahmad Sayasneh

Rebecca Kristeleit

Sophia Tsoka

James Spicer

Debra H. Josephs

Sophia N. Karagiannis

Abstract (eng)

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-?, 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, Fc?R-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 (eng)

HumansFemaleOvarian Neoplasms ImmunologyOvarian Neoplasms Drug TherapyOvarian Neoplasms PathologyT-Lymphocytes, Regulatory ImmunologyT-Lymphocytes, Regulatory Drug EffectsMacrophages ImmunologyMacrophages Drug EffectsImmunoglobulin E ImmunologyCarcinoma, Ovarian Epithelial ImmunologyCarcinoma, Ovarian Epithelial Drug TherapyReceptors, IgE MetabolismFolate Receptor 1 ImmunologyInflammation ImmunologyMiddle AgedCD8-Positive T-Lymphocytes Immunology

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4122

DOI

10.1038/s41467-025-57870-y

Is in series

Title (eng)

Nature Communications

Volume