Abstract
The efficacy of anthracycline chemotherapy depends on activation of type I IFN immune responses.
Major finding: The efficacy of anthracycline chemotherapy depends on activation of type I IFN immune responses.
Mechanism: Anthracyclines induce TLR3-mediated type I IFN–IFNAR signaling and CXCL10 secretion by cancer cells.
Impact: High expression of a type I IFN signature may predict successful anthracycline-based chemotherapy.
Anthracyclines are effective chemotherapeutic agents that function in part by eliciting anticancer immune responses. Sistigu, Yamazaki, Vacchelli, and colleagues hypothesized that the activity of anthracyclines may require type I IFN signaling, which is essential for the immune response to viral infections. Consistent with this idea, global transcriptome profiling of murine fibrosarcomas revealed that doxorubicin treatment increased the expression of IFN-stimulated genes associated with viral infection in neoplastic cells. Signaling of IFNαβ through the type I IFN receptor, IFNAR, in neoplastic but not host cells was required for the antitumor effects of anthracyclines. In addition, sarcomas deficient in toll-like receptor 3 (TLR3), an endosomal pattern recognition receptor, failed to instigate a type I IFN fingerprint following doxorubicin treatment and were unable to respond to anthracycline-based chemotherapy, suggesting that TLR3 activation by self-RNA released from dying cells is necessary for anthracycline-induced production of type I IFNs. In response to anthracyclines, type I IFN–IFNAR signaling stimulated autocrine and paracrine signaling and secretion of chemokine (C-X-C motif) ligand 10 (CXCL10), which plays an important role in antiviral and type I IFN immune responses, by both mouse and human tumor cells. Blockade of CXCL10 signaling abrogated the antitumor efficacy of doxorubicin, whereas administration of recombinant CXCL10 was sufficient to restore the sensitivity of IFNAR- and TLR-deficient sarcoma cells to doxorubicin. Exogenous type I IFNs also enhanced the sensitivity of tumor cells to cisplatin chemotherapy by stimulating protective IFNAR-mediated immune responses. Furthermore, high expression of a type I IFN signature was predictive of pathologic complete response to neoadjuvant anthracycline-based chemotherapy in patients with breast carcinoma and was associated with increased metastasis-free survival in patients with poor prognosis. These data demonstrate that anthracyclines mimic viral infection to induce optimal chemotherapeutic responses and suggest that type I IFN signaling may represent a useful clinical biomarker.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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