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: 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
• Journal: Nature medicine (Nat Med) Vol. 20 Issue 11 Pg. 1301-9 (Nov 2014) ISSN: 1546-170X [Electronic] United States
• PMID: 25344738 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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