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 M. Chenoweth, Lais C. G. F. Palhares, Theodore Evan, Jessica Hui Cheah Lim, Amanda L. Gross, Leonard 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
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.