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

A Sistigu, T Yamazaki, E Vacchelli, K Chaba, DP Enot… - Nature medicine, 2014 - nature.com
A Sistigu, T Yamazaki, E Vacchelli, K Chaba, DP Enot, J Adam, I Vitale, A Goubar…
Nature medicine, 2014nature.com
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 (CXC motif) ligand …
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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