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

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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Figure 1: A type I IFN signature in cancer cells is necessary for the therapeutic efficacy of doxorubicin.
Figure 2: TLR3-TICAM1 signaling is required for type I IFN release by cancer cells.
Figure 3: Role of CXCL10 in the anti-neoplastic activity of anthracyclines.
Figure 4: Improvement of chemotherapeutic responses by exogenous type I IFN.
Figure 5: MX1 expression in BC predicts pCR to neoadjuvant anthracycline-based chemotherapy.
Figure 6: Predictive value of MX1 expression in patients with BC treated with adjuvant chemotherapy.

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Acknowledgements

We acknowledge L. Galluzzi for help with preparation of the manuscript. We thank P. Rameau, Y. Lécluse and M. Sanchez for assistance with FACS experiments, G. Schiavoni and G. D'Agostino (Istituto Superiore di Sanità) for recombinant Ifn-α1, our colleagues from the Gustave Roussy Cancer Center and the Istituto Superiore di Sanità animal facilities, P. Gonin, M. Macchia and E. Cardarelli. We acknowledge P. Vielh for his help with immunohistochemical analyses and G. Stoll for his support in statistical analyses. G.K. and L.Z. are supported by the Ligue Nationale contre le Cancer (Equipes labellisées), Site de Recherche Intégrée sur le Cancer (IRIC) Socrates, the ISREC Foundation, Agence Nationale pour la Recherche (ANR AUTOPH, ANR Emergence), the European Commission (ArtForce), a European Research Council Advanced Investigator Grant (to G.K.), the Fondation pour la Recherche Médicale (FRM), the Institut National du Cancer (INCa), the Fondation de France, Cancéropôle Ile-de-France, the Fondation Bettencourt-Schueller, the LabEx Immuno-Oncology and the Paris Alliance of Cancer Research Institutes. A.S. is supported by Ligue Nationale contre le Cancer. D.H. was supported by Fondation Association pour la Recherche sur le Cancer. M.J.S. was supported by a National Health and Medical Research Council (NH&MRC) Australia Fellowship and Program Grant and a grant from the Victorian Cancer Agency. E.P. and L.B. were supported by Associazione Italiana Ricerca contro il Cancro (AIRC) (MFAG_13058). C.P. was supported by the Deutsche Forschungsgemeinschaft (DFG) PF809/1-1. C.E. was supported by Boerhinger Ingelheim. F.A. was supported by Association Vie et Cancer. J.A. was supported by Institut national du Cancer et la Direction Générale de l′Offre de Soins-INSERM 6043.

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A.S., T.Y., E.V., K.C., I.V., E.E.B., C.R., L.F., D.H., L. Aymeric, Y.M., M.N.-S., O.K., J.L.S., V.L.S., G.Z., P.S., F.U., M.P., C.E., C.P., M.J.S. and M.T.C. performed experiments. M.D., V.Q., R.C., J.-P.S., L.P., S.D., A.E. and F.A. enrolled patients in clinical trials. F.B., L.B. and E.P. directed part of A.S.'s experiments and supported the fees of the animal work. F.B., T.T., M.E.B., G.U. and R.D.S. provided reagents. L.Z. daily directed the two first authors and conceived the study. L.Z., F.A. and G.K. wrote the paper. V.P.-C. processed the TMAs and performed immunostaining of the biopsies and TMAs. A.G. and D.P.E. performed statistical analyses. J.A., S.L., L. Arnould, J.C., M.-C.D., F.P.-L. and M.L.-T. were the pathologists who interpreted the MX1 and TLR3 staining. X.P. and L.F. performed the experiments with transgenic oncolytic viruses.

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Correspondence to Guido Kroemer or Laurence Zitvogel.

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Sistigu, A., Yamazaki, T., Vacchelli, E. et al. Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med 20, 1301–1309 (2014). https://doi.org/10.1038/nm.3708

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