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.


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


  • 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