title: Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy.
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.
authors.affiliation: 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.
authors.forename: Antonella
authors.initials: A
authors.lastname: Sistigu
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. [3] INSERM, U848, Villejuif, France.
authors.forename: Erika
authors.initials: E
authors.lastname: Vacchelli
authors.affiliation: 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.
authors.forename: Kariman
authors.initials: K
authors.lastname: Chaba
authors.affiliation: 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.
authors.forename: David P
authors.initials: DP
authors.lastname: Enot
authors.affiliation: 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.
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Ilio
authors.initials: I
authors.lastname: Vitale
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U981, Villejuif, France.
authors.forename: Aicha
authors.initials: A
authors.lastname: Goubar
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. [3] INSERM, U848, Villejuif, France.
authors.forename: Elisa E
authors.initials: EE
authors.lastname: Baracco
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France.
authors.forename: Catarina
authors.initials: C
authors.lastname: Remédios
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Transgene S.A., Illkirch-Graffenstaden, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fend
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France.
authors.forename: Dalil
authors.initials: D
authors.lastname: Hannani
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U1015, Villejuif, France. [3] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Aymeric
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. [3] INSERM, U848, Villejuif, France.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Ma
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. [3] INSERM, U848, Villejuif, France.
authors.forename: Mireia
authors.initials: M
authors.lastname: Niso-Santano
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. [3] INSERM, U848, Villejuif, France.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.affiliation: Laboratory for Genomics and Immunoregulation, Life and Medical Sciences (LIMES), University of Bonn, Bonn, Germany.
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology, University Hospital Bonn, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bracci
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: La Sorsa
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ziccheddu
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Sestili
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Urbani
authors.affiliation: 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.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Department of Pathology, Centre Claudius Regaud, Toulouse, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Lacroix-Triki
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Quidville
authors.affiliation: 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.
authors.forename: Rosa
authors.initials: R
authors.lastname: Conforti
authors.affiliation: Department of Medical Oncology, Hôpital Pitie Salpetriere, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Spano
authors.affiliation: Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: 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.
authors.forename: Vichnou
authors.initials: V
authors.lastname: Poirier-Colame
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Department of Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Suzette
authors.initials: S
authors.lastname: Delaloge
authors.affiliation: Department of Pathology, Jean Perrin Center, EA 4677 ERTICa, University of Auvergne, Clermont-Ferrand, France.
authors.forename: Frederique
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: 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.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
authors.affiliation: 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.
authors.forename: Laurent
authors.initials: L
authors.lastname: Arnould
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] Department of Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Joanna
authors.initials: J
authors.lastname: Cyrta
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France. [2] INSERM, U981, Villejuif, France.
authors.forename: Marie-Charlotte
authors.initials: MC
authors.lastname: Dessoliers
authors.affiliation: Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.affiliation: San Raffaele University and Scientific Institute, Milan, Italy.
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.affiliation: 1] Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Mikael
authors.initials: M
authors.lastname: Pittet
authors.affiliation: 1] Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Camilla
authors.initials: C
authors.lastname: Engblom
authors.affiliation: 1] Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Pfirschke
authors.affiliation: Transgene S.A., Illkirch-Graffenstaden, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Préville
authors.affiliation: CNRS UMR5235, University Montpellier II, Place Eugène Bataillon, Montpellier, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Uzè
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.affiliation: Queensland Institute of Medical Research, Herston, Queensland, Australia.
authors.forename: Melvyn T
authors.initials: MT
authors.lastname: Chow
authors.affiliation: 1] Queensland Institute of Medical Research, Herston, Queensland, Australia. [2] School of Medicine, The University of Queensland, Herston, Queensland, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Proietti
authors.affiliation: 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.
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.affiliation: 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.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: 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.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D054357:Chemokine CXCL10 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007121:Immunocompetence / Q000187:drug effects; D007370:Interferon Type I / Q000096:biosynthesis / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D064547:Myxovirus Resistance Proteins / Q000378:metabolism; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018943:Anthracyclines; D054357:Chemokine CXCL10; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D051192:Receptors, Pattern Recognition; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D053633:Receptor, Interferon alpha-beta; D012313:RNA; D004317:Doxorubicin