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

Nature Medicine volume 20, pages 1301–1309 (2014)Cite this article

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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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Figure 1: A type I IFN signature in cancer cells is necessary for the therapeutic efficacy of doxorubicin.
Figure 2: TLR3-TICAM1 signaling is required for type I IFN release by cancer cells.
Figure 3: Role of CXCL10 in the anti-neoplastic activity of anthracyclines.
Figure 4: Improvement of chemotherapeutic responses by exogenous type I IFN.
Figure 5: MX1 expression in BC predicts pCR to neoadjuvant anthracycline-based chemotherapy.
Figure 6: Predictive value of MX1 expression in patients with BC treated with adjuvant chemotherapy.

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Acknowledgements

We acknowledge L. Galluzzi for help with preparation of the manuscript. We thank P. Rameau, Y. Lécluse and M. Sanchez for assistance with FACS experiments, G. Schiavoni and G. D'Agostino (Istituto Superiore di Sanità) for recombinant Ifn-α1, our colleagues from the Gustave Roussy Cancer Center and the Istituto Superiore di Sanità animal facilities, P. Gonin, M. Macchia and E. Cardarelli. We acknowledge P. Vielh for his help with immunohistochemical analyses and G. Stoll for his support in statistical analyses. G.K. and L.Z. are supported by the Ligue Nationale contre le Cancer (Equipes labellisées), Site de Recherche Intégrée sur le Cancer (IRIC) Socrates, the ISREC Foundation, Agence Nationale pour la Recherche (ANR AUTOPH, ANR Emergence), the European Commission (ArtForce), a European Research Council Advanced Investigator Grant (to G.K.), the Fondation pour la Recherche Médicale (FRM), the Institut National du Cancer (INCa), the Fondation de France, Cancéropôle Ile-de-France, the Fondation Bettencourt-Schueller, the LabEx Immuno-Oncology and the Paris Alliance of Cancer Research Institutes. A.S. is supported by Ligue Nationale contre le Cancer. D.H. was supported by Fondation Association pour la Recherche sur le Cancer. M.J.S. was supported by a National Health and Medical Research Council (NH&MRC) Australia Fellowship and Program Grant and a grant from the Victorian Cancer Agency. E.P. and L.B. were supported by Associazione Italiana Ricerca contro il Cancro (AIRC) (MFAG_13058). C.P. was supported by the Deutsche Forschungsgemeinschaft (DFG) PF809/1-1. C.E. was supported by Boerhinger Ingelheim. F.A. was supported by Association Vie et Cancer. J.A. was supported by Institut national du Cancer et la Direction Générale de l′Offre de Soins-INSERM 6043.

Author information

Author notes

  1. Antonella Sistigu, Takahiro Yamazaki and Erika Vacchelli: These authors contributed equally to this work.

  2. Fabrice André, Guido Kroemer and Laurence Zitvogel: These authors jointly supervised this work.

Authors and Affiliations

  1. Gustave Roussy Cancer Campus, Villejuif, France

    Antonella Sistigu, Takahiro Yamazaki, Erika Vacchelli, Julien Adam, Aicha Goubar, Elisa E Baracco, Catarina Remédios, Laetitia Fend, Dalil Hannani, Laetitia Aymeric, Yuting Ma, Mireia Niso-Santano, Oliver Kepp, Virginie Quidville, Rosa Conforti, Vichnou Poirier-Colame, Suzette Delaloge, Joanna Cyrta, Marie-Charlotte Dessoliers, Fabrice André, Guido Kroemer & Laurence Zitvogel

  2. INSERM, U1015, Villejuif, France

    Antonella Sistigu, Takahiro Yamazaki, Catarina Remédios, Laetitia Fend, Dalil Hannani, Laetitia Aymeric, Rosa Conforti & Vichnou Poirier-Colame

  3. Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France

    Antonella Sistigu, Takahiro Yamazaki, Erika Vacchelli, Elisa E Baracco, Catarina Remédios, Dalil Hannani, Laetitia Aymeric, Yuting Ma, Mireia Niso-Santano, Oliver Kepp, Alexander Eggermont, Fabrice André & Laurence Zitvogel

  4. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

    Antonella Sistigu, Filippo Belardelli, Laura Bracci, Valentina La Sorsa, Giovanna Ziccheddu, Paola Sestili, Francesca Urbani & Enrico Proietti

  5. INSERM, U848, Villejuif, France

    Erika Vacchelli, Kariman Chaba, David P Enot, Elisa E Baracco, Yuting Ma, Mireia Niso-Santano, Oliver Kepp & Guido Kroemer

  6. Equipe 11 Labellisée par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France

    Kariman Chaba & David P Enot

  7. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Kariman Chaba, David P Enot & Guido Kroemer

  8. Department of Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif, France

    Julien Adam, Suzette Delaloge, Joanna Cyrta & Fabrice André

  9. Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France

    Julien Adam, Virginie Quidville & Fabrice André

  10. Regina Elena National Cancer Institute, Rome, Italy

    Ilio Vitale

  11. INSERM, U981, Villejuif, France

    Aicha Goubar, Marie-Charlotte Dessoliers & Fabrice André

  12. Transgene S.A., Illkirch-Graffenstaden, France

    Laetitia Fend & Xavier Préville

  13. Laboratory for Genomics and Immunoregulation, Life and Medical Sciences (LIMES), University of Bonn, Bonn, Germany

    Joachim L Schultze

  14. Department of Dermatology, Laboratory of Experimental Dermatology, University Hospital Bonn, Bonn, Germany

    Thomas Tüting

  15. SIB–Swiss Institute of Bioinformatics, Lausanne, Switzerland

    Mauro Delorenzi

  16. 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

    Mauro Delorenzi

  17. Departement de Formation et Recherche, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

    Mauro Delorenzi

  18. Department of Pathology, Centre Claudius Regaud, Toulouse, France

    Magali Lacroix-Triki

  19. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France

    Rosa Conforti, Vichnou Poirier-Colame & Laurence Zitvogel

  20. Department of Medical Oncology, Hôpital Pitie Salpetriere, Paris, France

    Rosa Conforti & Jean-Philippe Spano

  21. Yale School of Medicine, New Haven, Connecticut, USA

    Lajos Pusztai

  22. Department of Pathology, Jean Perrin Center, EA 4677 ERTICa, University of Auvergne, Clermont-Ferrand, France

    Frederique Penault-Llorca

  23. Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France

    Sylvain Ladoire & Laurent Arnould

  24. INSERM, CRI-866 Faculty of Medicine, Dijon, France

    Sylvain Ladoire & Laurent Arnould

  25. University of Burgundy, Dijon, France

    Sylvain Ladoire & Laurent Arnould

  26. San Raffaele University and Scientific Institute, Milan, Italy

    Marco E Bianchi

  27. Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts, USA

    Mikael Pittet, Camilla Engblom & Christina Pfirschke

  28. Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA

    Mikael Pittet, Camilla Engblom & Christina Pfirschke

  29. CNRS UMR5235, University Montpellier II, Place Eugène Bataillon, Montpellier, France

    Gilles Uzè

  30. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

    Robert D Schreiber

  31. Queensland Institute of Medical Research, Herston, Queensland, Australia

    Melvyn T Chow & Mark J Smyth

  32. School of Medicine, The University of Queensland, Herston, Queensland, Australia

    Mark J Smyth

  33. Metabolomics Platform, Gustave Roussy Cancer Campus, Villejuif, France

    Guido Kroemer

  34. Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France

    Guido Kroemer

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  1. Antonella Sistigu
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  2. Takahiro Yamazaki
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Contributions

A.S., T.Y., E.V., K.C., I.V., E.E.B., C.R., L.F., D.H., L. Aymeric, Y.M., M.N.-S., O.K., J.L.S., V.L.S., G.Z., P.S., F.U., M.P., C.E., C.P., M.J.S. and M.T.C. performed experiments. M.D., V.Q., R.C., J.-P.S., L.P., S.D., A.E. and F.A. enrolled patients in clinical trials. F.B., L.B. and E.P. directed part of A.S.'s experiments and supported the fees of the animal work. F.B., T.T., M.E.B., G.U. and R.D.S. provided reagents. L.Z. daily directed the two first authors and conceived the study. L.Z., F.A. and G.K. wrote the paper. V.P.-C. processed the TMAs and performed immunostaining of the biopsies and TMAs. A.G. and D.P.E. performed statistical analyses. J.A., S.L., L. Arnould, J.C., M.-C.D., F.P.-L. and M.L.-T. were the pathologists who interpreted the MX1 and TLR3 staining. X.P. and L.F. performed the experiments with transgenic oncolytic viruses.

Corresponding authors

Correspondence to Guido Kroemer or Laurence Zitvogel.

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Competing interests

The authors declare no competing financial interests.

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Supplementary Figures 1–9 and Supplementary Tables 1–6 (PDF 1245 kb)

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Sistigu, A., Yamazaki, T., Vacchelli, E. et al. Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med 20, 1301–1309 (2014). https://doi.org/10.1038/nm.3708

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  • DOI: https://doi.org/10.1038/nm.3708

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