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Dual oxidase 1 limits the IFNγ-associated antitumor effect of macrophages
Lydia Meziani1,2, Marine Gerbé de Thoré3,2, Pauline Hamon3,2
1INSERM U1030, Molecular Radiotherapy, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France lydia.meziani@gustaveroussy.fr.
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:
Using 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.
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.
Insights
Dual oxidase 1 (DUOX1) in macrophages impairs antitumor responses. Inhibiting DUOX1 in macrophages enhances radiotherapy efficacy, offering a novel cancer treatment strategy.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Macrophages are crucial in tumor progression and response to cancer therapies like radiotherapy (RT).
- Dual oxidase 1 (DUOX1) is a transmembrane enzyme vital for oxidant generation.
- DUOX1 expression was observed in macrophages from human lung samples after ionizing radiation exposure.
Purpose of the Study:
- To investigate the role of DUOX1 in macrophage activation.
- To determine the impact of DUOX1-expressing macrophages on tumor development.
- To explore DUOX1 as a potential therapeutic target in cancer treatment.
Main Methods:
- Utilized Duox1 knockout mice to study the absence of DUOX1 in proinflammatory macrophages.
- Administered intratumoral injections of Duox1-deficient proinflammatory macrophages.
- Performed in vitro and in vivo assessments of macrophage function, cytokine production, and major histocompatibility complex class II expression.
Main Results:
- Lack of DUOX1 in proinflammatory macrophages enhanced their antitumor effects.
- Intratumoral injection of Duox1-deficient macrophages significantly boosted RT's antitumor efficacy.
- DUOX1 deficiency increased proinflammatory cytokine production (IFNγ, CXCL9, CCL3, TNFα) and MHC class II expression in activated macrophages.
- DUOX1 was implicated in macrophage phagocytotic function.
- Antitumor effects correlated with increased IFNγ production by immune cells.
Conclusions:
- DUOX1 represents a new target for reprogramming macrophages.
- Inhibiting DUOX1 in macrophages, combined with RT, presents a promising therapeutic strategy for cancer management.
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