TLR4/IFNγ pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models. (3rd May 2016)

• Record Type: Journal Article
• Authors: Lamrani, Myriam; Sassi, Nejia; Paul, Catherine; Yousfi, Nadhir; Boucher, Jean-Luc; Gauthier, Nolwenn; Labbé, Jérôme; Seignez, Cédric; Racoeur, Cindy; Athias, Anne; Guerreiro, Romain; Vergely, Catherine; Rochette, Luc; Bettaieb, Ali; Jeannin, Jean-François
• Is Part Of: Oncoimmunology. Volume 5:Number 5(2016)
• Publication Date: 2016-05-03
• Subjects: Interferon gamma -- lipid A -- mammary or breast cancer -- nitric oxide -- NOS II uncoupling -- OM-174 -- peroxynitrite -- ROS; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2015.1123369
• Languages: English
• ISSNs: 2162-402X

Abstract

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 γ (IFNγ) or TLR4. TLR4 and IFNγ 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 IFNγ 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 IFNγ-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/IFNγ/NOS II pathway in immunotherapy was investigated.