Journal Article

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

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

2014

Overview

Anthracyclines can induce a type 1 interferon response in tumor cells that may predict clinical response to these drugs. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 14 / 38 / 42 / 45 / 49 / 631/250 / 631/250/580/1884/2323 / 64 / 82 / 96 / Adaptor Proteins, Vesicular Transport - metabolism / Analysis / Animals / Anthracyclines / Anthracyclines - pharmacology / Anthracyclines - therapeutic use / Biomedicine / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - immunology / Breast Neoplasms - pathology / Cancer / Cancer cells / Cancer Research / Care and treatment / Chemokine CXCL10 - metabolism / Chemokines / Chemotherapy / Doxorubicin - pharmacology / Doxorubicin - therapeutic use / Female / Gene Expression Regulation, Neoplastic - drug effects / Health aspects / Humans / Immunocompetence - drug effects / Immunology / Immunotherapy / Infectious Diseases / Interferon / Interferon Type I - biosynthesis / Interferon Type I - metabolism / Life Sciences / Metabolic Diseases / Mice, Inbred C57BL / Molecular Medicine / Myxovirus Resistance Proteins - metabolism / Neoadjuvant Therapy / Neoplasm Metastasis / Neurosciences / Pathogens / Pattern recognition / Physiological aspects / Receptor, Interferon alpha-beta - metabolism / Receptors, Pattern Recognition - metabolism / RNA - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / Signal transduction / Signal Transduction - drug effects / Testing / Toll-Like Receptor 3 - metabolism / Treatment Outcome