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

Antonella Sistigu; Takahiro Yamazaki; Erika Vacchelli; Kariman Chaba; David P Enot; Julien Adam; Ilio Vitale; Aicha Goubar; Elisa E Baracco; Catarina Remédios; Laetitia Fend; Dalil Hannani; Laetitia Aymeric; Yuting Ma; Mireia Niso-Santano; Oliver Kepp; Joachim L Schultze; Thomas Tüting; Filippo Belardelli; Laura Bracci; Valentina La Sorsa; Giovanna Ziccheddu; Paola Sestili; Francesca Urbani; Mauro Delorenzi; Magali Lacroix-Triki; Virginie Quidville; Rosa Conforti; Jean-Philippe Spano; Lajos Pusztai; Vichnou Poirier-Colame; Suzette Delaloge; Frederique Penault-Llorca; Sylvain Ladoire; Laurent Arnould; Joanna Cyrta; Marie-Charlotte Dessoliers; Alexander Eggermont; Marco E Bianchi; Mikael Pittet; Camilla Engblom; Christina Pfirschke; Xavier Préville; Gilles Uzè; Robert D Schreiber; Melvyn T Chow; Mark J Smyth; Enrico Proietti; Fabrice André; Guido Kroemer; Laurence Zitvogel

doi:10.1038/nm.3708

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

Nat Med. 2014 Nov;20(11):1301-9. doi: 10.1038/nm.3708. Epub 2014 Oct 26.

Authors

Antonella Sistigu¹, Takahiro Yamazaki², Erika Vacchelli³, Kariman Chaba⁴, David P Enot⁴, Julien Adam⁵, Ilio Vitale⁶, Aicha Goubar⁷, Elisa E Baracco³, Catarina Remédios², Laetitia Fend⁸, Dalil Hannani², Laetitia Aymeric², Yuting Ma³, Mireia Niso-Santano³, Oliver Kepp³, Joachim L Schultze⁹, Thomas Tüting¹⁰, Filippo Belardelli¹¹, Laura Bracci¹¹, Valentina La Sorsa¹¹, Giovanna Ziccheddu¹¹, Paola Sestili¹¹, Francesca Urbani¹¹, Mauro Delorenzi¹², Magali Lacroix-Triki¹³, Virginie Quidville¹⁴, Rosa Conforti¹⁵, Jean-Philippe Spano¹⁶, Lajos Pusztai¹⁷, Vichnou Poirier-Colame¹⁸, Suzette Delaloge¹⁹, Frederique Penault-Llorca²⁰, Sylvain Ladoire²¹, Laurent Arnould²¹, Joanna Cyrta¹⁹, Marie-Charlotte Dessoliers⁷, Alexander Eggermont²², Marco E Bianchi²³, Mikael Pittet²⁴, Camilla Engblom²⁴, Christina Pfirschke²⁴, Xavier Préville²⁵, Gilles Uzè²⁶, Robert D Schreiber²⁷, Melvyn T Chow²⁸, Mark J Smyth²⁹, Enrico Proietti¹¹, Fabrice André³⁰, Guido Kroemer³¹, Laurence Zitvogel³²

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.

PMID: 25344738
DOI: 10.1038/nm.3708

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.

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Vesicular Transport / metabolism
Animals
Anthracyclines / pharmacology
Anthracyclines / therapeutic use
Breast Neoplasms / drug therapy*
Breast Neoplasms / genetics
Breast Neoplasms / immunology
Breast Neoplasms / pathology*
Chemokine CXCL10 / metabolism
Doxorubicin / pharmacology
Doxorubicin / therapeutic use*
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Immunocompetence / drug effects
Interferon Type I / biosynthesis
Interferon Type I / metabolism*
Mice, Inbred C57BL
Myxovirus Resistance Proteins / metabolism
Neoadjuvant Therapy
Neoplasm Metastasis
RNA / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptor, Interferon alpha-beta / metabolism
Receptors, Pattern Recognition / metabolism
Signal Transduction* / drug effects
Toll-Like Receptor 3 / metabolism
Treatment Outcome

Substances

Adaptor Proteins, Vesicular Transport
Anthracyclines
Chemokine CXCL10
Ifnar1 protein, mouse
Interferon Type I
MX1 protein, human
Myxovirus Resistance Proteins
RNA, Messenger
Receptors, Pattern Recognition
TLR3 protein, mouse
Toll-Like Receptor 3
Receptor, Interferon alpha-beta
RNA
Doxorubicin