Dual oxidase 1 limits the IFNγ-associated antitumor effect of macrophages

• Published in: Journal for immunotherapy of cancer Vol. 8; no. 1; p. e000622
• Main Authors: Meziani, Lydia, Gerbé de Thoré, Marine, Hamon, Pauline, Bockel, Sophie, Andrade Louzada, Ruy, Clemenson, Céline, Corre, Raphaël, Liu, Wincgygn, Dupuy, Corinne, Mondini, Michele, Deutsch, Eric
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group LTD 01-06-2020; BMJ Publishing Group
• Series: Original research
• Subjects: Adaptive immunology; Antibodies; Bone marrow; Cancer; Chemokines; Cytokines; Experiments; Flow cytometry; Immune Cell Therapies and Immune Cell Engineering; Immunology; Immunotherapy; Innate immunity; Laboratory animals; Life Sciences; Lymphocytes; Pathogens; Software; Tumors; France
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2020-000622

BackgroundMacrophages play pivotal roles in tumor progression and the response to anticancer therapies, including radiotherapy (RT). Dual oxidase (DUOX) 1 is a transmembrane enzyme that plays a critical role in oxidant generation.MethodsSince we found DUOX1 expression in macrophages from human lung samples exposed to ionizing radiation, we aimed to assess the involvement of DUOX1 in macrophage activation and the role of these macrophages in tumor development.ResultsUsing Duox1−/− mice, we demonstrated that the lack of DUOX1 in proinflammatory macrophages improved the antitumor effect of these cells. Furthermore, intratumoral injection of Duox1−/− proinflammatory macrophages significantly enhanced the antitumor effect of RT. Mechanistically, DUOX1 deficiency increased the production of proinflammatory cytokines (IFNγ, CXCL9, CCL3 and TNFα) by activated macrophages in vitro and the expression of major histocompatibility complex class II in the membranes of macrophages. We also demonstrated that DUOX1 was involved in the phagocytotic function of macrophages in vitro and in vivo. The antitumor effect of Duox1−/− macrophages was associated with a significant increase in IFNγ production by both lymphoid and myeloid immune cells.ConclusionsOur data indicate that DUOX1 is a new target for macrophage reprogramming and suggest that DUOX1 inhibition in macrophages combined with RT is a new therapeutic strategy for the management of cancers.