Gabriel Osborn Gabriel Osborn Jacobo López-Abente Jacobo López-Abente Rebecca Adams Rebecca Adams Roman Laddach Roman Laddach Melanie Grandits Melanie Grandits Heather J. Bax Heather J. Bax Jitesh Chauhan Jitesh Chauhan Giulia Pellizzari Giulia Pellizzari Mano Nakamura Mano Nakamura Chara Stavraka Chara Stavraka Alicia Chenoweth Alicia Chenoweth Lais C. G. F. Palhares Lais C. G. F. Palhares Theodore Evan Theodore Evan Jessica Hui Cheah Lim Jessica Hui Cheah Lim Amanda Gross Amanda Gross Lenny Moise Lenny Moise Shashi Jatiani Shashi Jatiani Mariangela Figini Mariangela Figini Rodolfo Bianchini Rodolfo Bianchini Erika Jensen-Jarolim Erika Jensen-Jarolim Sharmistha Ghosh Sharmistha Ghosh Ana Montes Ana Montes Ahmad Sayasneh Ahmad Sayasneh Rebecca Kristeleit Rebecca Kristeleit Sophia Tsoka Sophia Tsoka James Spicer James Spicer Debra H. Josephs Debra H. Josephs Sophia N. Karagiannis Sophia N. Karagiannis Nature Portfolio 2025 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. PDFDocument eng 2025-05-09T08:32:33.354800Z 2025 Humans Female Ovarian Neoplasms Immunology Ovarian Neoplasms Drug Therapy Ovarian Neoplasms Pathology T-Lymphocytes, Regulatory Immunology T-Lymphocytes, Regulatory Drug Effects Macrophages Immunology Macrophages Drug Effects Immunoglobulin E Immunology Carcinoma, Ovarian Epithelial Immunology Carcinoma, Ovarian Epithelial Drug Therapy Receptors, IgE Metabolism Folate Receptor 1 Immunology Inflammation Immunology Middle Aged CD8-Positive T-Lymphocytes Immunology 8001428 b application/pdf http://creativecommons.org/licenses/by/4.0/