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

Background Macrophages 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. Methods Since 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. Results UsingDuox1(-/-)mice, we demonstrated that the lack of DUOX1 in proinflammatory macrophages improved the antitumor effect of these cells. Furthermore, intratumoral injection ofDuox1(-/-)proinflammatory macrophages significantly enhanced the antitumor effect of RT. Mechanistically, DUOX1 deficiency increased the production of proinflammatory cytokines (IFN gamma, CXCL9, CCL3 and TNF alpha) by activated macrophagesin vitroand 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 macrophagesin vitroandin vivo. The antitumor effect ofDuox1(-/-)macrophages was associated with a significant increase in IFN gamma production by both lymphoid and myeloid immune cells. Conclusions Our 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.