Editors' ChoiceCancer

Tumor Cell–Intrinsic Interferon Chemotherapy

Sci. Signal.  25 Nov 2014:
Vol. 7, Issue 353, pp. ec329
DOI: 10.1126/scisignal.aaa3417

The secretion of type I interferons (IFN-α and IFN-β), which is stimulated by the activation of pattern-recognition recep­tors [such as Toll-like receptor 3 (TLR3)], has a central role in the innate immune response against viral infection. The effects of some chemotherapeutics, including anthracyclines, are associated with the induction of anticancer immune responses. Sistigu et al. found that type I IFN signaling in tumor cells mediated the cytotoxic response to anthracyclines, which inhibit DNA and RNA synthesis by intercalating into DNA or RNA and inhibit topoisomerase II. When fibrosarcomas in mice were injected intratumorally with the anthracycline doxorubicin, the abundance of IFN-stimulated transcripts associated with viral infection, including the transcript for the chemokine CXCL10, increased in the tumor cells. A panel of human or mouse cancer cell lines had a similar expression signature when exposed to doxorubicin or mitoxantrone (another anthracycline) but not to DNA cross-linking agents, such as cisplatin. However, this signature was not observed in sarcomas obtained from mice lacking Tlr3 or the gene encoding its adaptor TRIF. The type I IFN receptor (IFNAR) consists of the subunits IFNAR1 and IFNAR2. Doxorubicin induced the secretion of IFN-β1 from sarcoma cells from wild-type mice but not from mice lacking Ifnar2, Tlr3, or Trif. Likewise, doxorubicin reduced the growth of mammary carcinomas and fibrosarcomas transplanted from wild-type mice into either wild-type or Ifnar1-/- mice but did not reduce the growth of tumors in mice treated with function-blocking antibodies to IFNAR1 or CXCR3 (the main CXCL10 receptor) or when tumors originated from Ifnar1-/-, Ifnar2-/-, or Tlr3-/- mice. These data suggested that doxorubicin induced an IFN-mediated response within the tumor cells. Intratumoral injection of exogenous IFN-α and IFN-β enhanced the effects of cisplatin (which did not induce the IFN response on its own) against fibrosarcoma and melanoma in immunocompetent mice. In patients with breast carcinoma, a type I IFN-related expression signature correlated with clinical efficacy of anthracycline-based chemotherapy. The findings suggest that type I IFN signaling in tumor cells mediates the response to anthracyclines and that the efficacy of other chemotherapeutics may be enhanced by promoting type I IFN signaling in tumors.

A. Sistigu, T. Yamazaki, E. Vacchelli, K. Chaba, D. P. Enot, J. Adam, I. Vitale, A. Goubar, E. E. Baracco, C. Remédios, L. Fend, D. Hannani, L. Aymeric, Y. Ma, M. Niso-Santano, O. Kepp, J. L. Schultze, T. Tüting, F. Belardelli, L. Bracci, V. La Sorsa, G. Ziccheddu, P. Sestili, F. Urbani, M. Delorenzi, M. Lacroix-Triki, V. Quidville, R. Conforti, J.-P. Spano, L. Pusztai, V. Poirier-Colame, S. Delaloge, F. Penault-Llorca, S. Ladoire, L. Arnould, J. Cyrta, M.-C. Dessoliers, A. Eggermont, M. E. Bianchi, M. Pittet, C. Engblom, C. Pfirschke, X. Préville, G. Uzè, R. D. Schreiber, M. T. Chow, M. J. Smyth, E. Proietti, F. André, G. Kroemer, L. Zitvogel, Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat. Med. 20, 1301–1309 (2014). [PubMed]