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

Nat Med 2014 Nov 26;20(11):1301-9. Epub 2014 Oct 26.

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.

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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November 2014
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