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TLR4/IFNγ pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models

Abstract : Toll-like receptor (TLR) 4 agonists have emerged as a new group of molecules used for cancer therapy. They have been exploited to enhance the immunogenicity of current chemotherapeutic regimens. However, their effects on cancer cells remain elusive. Here, we showed that a TLR4 agonist, namely a synthetic lipid A analog (ALA), OM-174, exhibits antitumor effects in several mammary tumor mouse models. We also showed that immune components are involved in such effects, as attested to by the failure of ALA to induce tumor regression or an increase of animal survival in mice knocked-out for interferon g (IFNg) or TLR4. TLR4 and IFNg receptor (INFR2) expressed by cancer cells are involved in the antitumor efficacy of ALA since this last did not inhibit tumor growth in mice bearing a tumor but lacking TLR4 or IFNg receptor 2 (IFNR2). Mechanistic investigations revealed that nitric oxide (NO), superoxide and peroxynitrite produced by uncoupling of inducible NO synthase (NOS II) in cancer cells are key mediators of ALA and IFNg-mediated tumor growth inhibition. We present here a comprehensive picture of tumor cell death induction, in vivo and in vitro, by immunotherapy and for the first time the involvement of the TLR4/IFNg/NOS II pathway in immunotherapy was investigated.
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Contributeur : Catherine Vergely Connectez-vous pour contacter le contributeur
Soumis le : mercredi 17 novembre 2021 - 17:02:46
Dernière modification le : mercredi 28 septembre 2022 - 16:20:11
Archivage à long terme le : : vendredi 18 février 2022 - 20:46:19


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Myriam Lamrani, Nejia Sassi, Catherine Paul, Nadhir Yousfi, Jean-Luc Boucher, et al.. TLR4/IFNγ pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models. OncoImmunology, Taylor & Francis, 2016, 5 (5), pp.e1123369. ⟨10.1080/2162402x.2015.1123369⟩. ⟨hal-03433384⟩



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