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      Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy.

      1 , 2 , 3 , 4 , 4 , 5 , 6 , 7 , 3 , 2 , 8 , 2 , 2 , 3 , 3 , 3 , 9 , 10 , 11 , 11 , 11 , 11 , 11 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 21 , 19 , 7 , 22 , 23 , 24 , 24 , 24 , 25 , 26 , 27 , 28 , 29 , 11 , 30 , 31 , 32
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          Abstract

          Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy.

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          Author and article information

          Journal
          Nat. Med.
          Nature medicine
          1546-170X
          1078-8956
          Nov 2014
          : 20
          : 11
          Affiliations
          [1 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. [4] Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
          [2 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France.
          [3 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. [3] INSERM, U848, Villejuif, France.
          [4 ] 1] INSERM, U848, Villejuif, France. [2] Equipe 11 Labellisée par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
          [5 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Department of Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif, France. [3] Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
          [6 ] Regina Elena National Cancer Institute, Rome, Italy.
          [7 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U981, Villejuif, France.
          [8 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Transgene S.A., Illkirch-Graffenstaden, France.
          [9 ] Laboratory for Genomics and Immunoregulation, Life and Medical Sciences (LIMES), University of Bonn, Bonn, Germany.
          [10 ] Laboratory of Experimental Dermatology, Department of Dermatology, University Hospital Bonn, Bonn, Germany.
          [11 ] Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
          [12 ] 1] SIB-Swiss Institute of Bioinformatics, Lausanne, Switzerland. [2] National Center of Competence in Research (NCCR) Molecular Oncology, Institut Suisse de Recherche Expérimentale sur le Cancer (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. [3] Departement de Formation et Recherche, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
          [13 ] Department of Pathology, Centre Claudius Regaud, Toulouse, France.
          [14 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
          [15 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France. [4] Department of Medical Oncology, Hôpital Pitie Salpetriere, Paris, France.
          [16 ] Department of Medical Oncology, Hôpital Pitie Salpetriere, Paris, France.
          [17 ] Yale School of Medicine, New Haven, Connecticut, USA.
          [18 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.
          [19 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Department of Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif, France.
          [20 ] Department of Pathology, Jean Perrin Center, EA 4677 ERTICa, University of Auvergne, Clermont-Ferrand, France.
          [21 ] 1] Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France. [2] INSERM, CRI-866 Faculty of Medicine, Dijon, France. [3] University of Burgundy, Dijon, France.
          [22 ] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France.
          [23 ] San Raffaele University and Scientific Institute, Milan, Italy.
          [24 ] 1] Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
          [25 ] Transgene S.A., Illkirch-Graffenstaden, France.
          [26 ] CNRS UMR5235, University Montpellier II, Place Eugène Bataillon, Montpellier, France.
          [27 ] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
          [28 ] Queensland Institute of Medical Research, Herston, Queensland, Australia.
          [29 ] 1] Queensland Institute of Medical Research, Herston, Queensland, Australia. [2] School of Medicine, The University of Queensland, Herston, Queensland, Australia.
          [30 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. [3] Department of Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif, France. [4] Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France. [5] INSERM, U981, Villejuif, France.
          [31 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U848, Villejuif, France. [3] Université Paris Descartes, Sorbonne Paris Cité, Paris, France. [4] Metabolomics Platform, Gustave Roussy Cancer Campus, Villejuif, France. [5] Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
          [32 ] 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. [3] Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.
          Article
          nm.3708
          10.1038/nm.3708
          25344738
          40fc2ea2-26f1-417b-8ca2-d8620ea2682a
          History

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