Although tumor-associated macrophages have been extensively studied in the control of response to radiotherapy, the molecular mechanisms involved in the
ionizing radiation-mediated activation of macrophages remain elusive. Here the present inventors show that
ionizing radiation induces the expression of
interferon-regulatory factor 5 (IRF5) promoting thus macrophage activation toward a pro-inflammatory
phenotype. They reveal that the activation of the
Ataxia telangiectasia mutated (ATM)
kinase is required for
ionizing radiation-elicited macrophage activation, but also for macrophage
reprogramming after treatments with γ-
interferon,
lipopolysaccharide or chemotherapeutic agent (such as cis-platin), underscoring the fact that the
kinase ATM plays a central role during macrophage phenotypic switching toward a proinflammatory
phenotype. They further demonstrate that
NADPH oxidase 2 (
NOX2)-dependent ROS production is upstream to ATM activation and is essential during this process. They also report that hypoxic conditions and the inhibition of any component of this signaling pathway (
NOX2, ROS and ATM) impairs pro-inflammatory activation of macrophages and predicts a poor
tumor response to preoperative radiotherapy in
locally advanced rectal
cancer. Altogether, these results identify a novel signaling pathway involved in macrophage activation that may enhance effectiveness of radiotherapy through the re-
programming of tumor infiltrating macrophages.