title: 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 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.
authors.affiliation: EPHE, PSL Research University, Laboratoire d'Immunologie et Immunothérapie des Cancers, F-75014, Paris, France; Univ. Bourgogne Franche-Comté, LIIC EA7269, Dijon, France; INSERM U 866, Burgundy University, Dijon, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Lamrani
authors.affiliation: EPHE, PSL Research University, Laboratoire d'Immunologie et Immunothérapie des Cancers, F-75014, Paris, France; Univ. Bourgogne Franche-Comté, LIIC EA7269, Dijon, France; INSERM U 866, Burgundy University, Dijon, France.
authors.forename: Nejia
authors.initials: N
authors.lastname: Sassi
authors.affiliation: EPHE, PSL Research University, Laboratoire d'Immunologie et Immunothérapie des Cancers, F-75014, Paris, France; Univ. Bourgogne Franche-Comté, LIIC EA7269, Dijon, France; INSERM U 866, Burgundy University, Dijon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Paul
authors.affiliation: EPHE, PSL Research University, Laboratoire d'Immunologie et Immunothérapie des Cancers, F-75014, Paris, France; Univ. Bourgogne Franche-Comté, LIIC EA7269, Dijon, France.
authors.forename: Nadhir
authors.initials: N
authors.lastname: Yousfi
authors.affiliation: UMR 8601 CNRS, Paris Descartes University , Paris, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Boucher
authors.affiliation: EPHE, PSL Research University, Laboratoire d'Immunologie et Immunothérapie des Cancers, F-75014, Paris, France; INSERM U 866, Burgundy University, Dijon, France.
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Gauthier
authors.affiliation: EPHE, PSL Research University, Laboratoire d'Immunologie et Immunothérapie des Cancers, F-75014, Paris, France; INSERM U 866, Burgundy University, Dijon, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Labbé
authors.affiliation: EPHE, PSL Research University, Laboratoire d'Immunologie et Immunothérapie des Cancers, F-75014, Paris, France; Univ. Bourgogne Franche-Comté, LIIC EA7269, Dijon, France; INSERM U 866, Burgundy University, Dijon, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Seignez
authors.affiliation: EPHE, PSL Research University, Laboratoire d'Immunologie et Immunothérapie des Cancers, F-75014, Paris, France; Univ. Bourgogne Franche-Comté, LIIC EA7269, Dijon, France; INSERM U 866, Burgundy University, Dijon, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Racoeur
authors.affiliation: INSERM U 866, Burgundy University , Dijon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Athias
authors.affiliation: BioGéoSciences UMR 6282, Burgundy University , Dijon, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Guerreiro
authors.affiliation: INSERM U 866, Burgundy University , Dijon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vergely
authors.affiliation: INSERM U 866, Burgundy University , Dijon, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Rochette
authors.affiliation: EPHE, PSL Research University, Laboratoire d'Immunologie et Immunothérapie des Cancers, F-75014, Paris, France; Univ. Bourgogne Franche-Comté, LIIC EA7269, Dijon, France; INSERM U 866, Burgundy University, Dijon, France.
authors.forename: Ali
authors.initials: A
authors.lastname: Bettaieb
authors.affiliation: EPHE, PSL Research University, Laboratoire d'Immunologie et Immunothérapie des Cancers, F-75014, Paris, France; Univ. Bourgogne Franche-Comté, LIIC EA7269, Dijon, France; INSERM U 866, Burgundy University, Dijon, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Jeannin
keywords: Interferon gamma; NOS II uncoupling; OM-174; ROS; lipid A; mammary or breast cancer; nitric oxide; peroxynitrite