Journal Article

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

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

2025

Overview

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. An IgE antibody recognising Folate Receptor-alpha has been tested in clinical trials for ovarian cancer and preclinical studies show macrophage involvement in the anti-tumoural functions of IgE. Here the authors demonstrate that IgE induces proinflammatory activation of ovarian cancer patient macrophages, which reverses their immunosuppressive induction of Treg cells and promotes CD8 + T cell function.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/31 / 13/51 / 38/91 / 631/250/2152/2153/1291 / 631/250/2504/342 / 631/250/251 / 631/250/2520 / 631/67/1059/2325 / 64/86 / 82/1 / Antibodies / Anticancer properties / Cancer / Carcinoma, Ovarian Epithelial - drug therapy / Carcinoma, Ovarian Epithelial - immunology / CD3 antigen / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Clinical trials / Female / Flow cytometry / Folate Receptor 1 - immunology / Folic acid / Humanities and Social Sciences / Humans / Immunoglobulin E / Immunoglobulin E - immunology / Immunosuppression / Inflammation / Inflammation - immunology / Lymphocytes / Lymphocytes T / Macrophages / Macrophages - drug effects / Macrophages - immunology / Metastases / Middle Aged / multidisciplinary / Ovarian cancer / Ovarian Neoplasms - drug therapy / Ovarian Neoplasms - immunology / Ovarian Neoplasms - pathology / Patients / Phenotypes / Receptors / Receptors, IgE - metabolism / Science / Science (multidisciplinary) / T-Lymphocytes, Regulatory - drug effects / T-Lymphocytes, Regulatory - immunology / Tumors