Institut Gustave Roussy

Institut National De La Sante Et De La Recherche Medicale

Institut Pasteur

Université Paris Descartes

Université Paris—sud

Université Pierre Et Marie Curie

Assistance Publique - Hopitaux De Paris (Aphp)

Instituto Nazionale Per Le Malattie Infettie Irccs Lazzaro Spallanzani

Awatef Allouch

Jean-Luc Perfettini

Guido Kroemer

Marie-Lise Gougeon

Eric Deutsch

Mauro Piacentini

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 &#x3b3;-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.

NOX2 as a biomarker of radiotherapy efficiency in cancer patients

The present invention provides methods and pharmaceutical compositions for treating human immunodeficiency virus type 1 (HIV-1) infections. In particular, the present invention relates to a method for treating HIV-1 infection in a subject in need thereof comprising administering the subject with a therapeutically effective amount of an inhibitor of SGT1 activity or expression.

Methods and pharmaceutical compositions for treating human immunodeficiency virus type 1 (HIV-1) infections

Growing community of inventors

Villejuif, France

Awatef Allouch