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

Abstract

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.

Journal

Journal ID (nlm-ta): J Immunother Cancer

Journal ID (iso-abbrev): J Immunother Cancer

Journal ID (hwp): jitc

Journal ID (publisher-id): jitc

Title: Journal for Immunotherapy of Cancer

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2051-1426

Publication date Collection: 2020

Publication date (Electronic): 21 June 2020

Volume: 8

Issue: 1

Affiliations

[1 ] INSERM U1030, Molecular Radiotherapy, Gustave Roussy Cancer Campus, Université Paris-Saclay , Villejuif, France

[2 ] Labex LERMIT, DHU TORINO, SIRIC SOCRATE , Villejuif, France

[3 ] departmentCNRS UMR 8200 , Gustave Roussy Cancer Campus, Université Paris-Saclay , Villejuif, France

[4 ] Department of Radiation Oncology, Gustave Roussy Cancer Campus , Villejuif, France

Author notes

[Correspondence to ] Dr Lydia Meziani; lydia.meziani@ 123456gustaveroussy.fr

MM and ED are joint senior authors.

Article

Publisher ID: jitc-2020-000622

DOI: 10.1136/jitc-2020-000622

PMC ID: 7307581

Copyright statement: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

Product

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100006364, Institut National Du Cancer;

Award ID: INCA 2014-1-PL-BIO-03

Categories

Subject: Immune Cell Therapies and Immune Cell Engineering

Subject: 1506

Subject: 2436

Series title: Original research

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