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Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy

Abstract

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen–specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.

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Figure 1: TLR4 controls antigen presentation by DCs engulfing apoptotic bodies in vitro.
Figure 2: TLR4 expression by DCs is required for the immune response against dying tumor cells in vivo.
Figure 3: The immunogenicity of dying tumor cells after chemotherapy or radiotherapy depends on the release of the TLR4 ligand HMGB1.
Figure 4: TLR4 and its ligand HMGB1 are both required for the success of vaccination against tumor cells.
Figure 5: TLR4 dictates the efficacy of antitumor chemotherapy and radiotherapy in mice.
Figure 6: TLR4 dictates the efficacy of antitumor chemotherapy in humans.

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Acknowledgements

We thank P. Aucouturier for helpful discussions; P. Tiberghien for providing DNA samples for genotyping; E. Vicaut for help in statistical analyses; S. Viaud and C. Chenot for technical assistance; the IGR animal facility for help in breeding transgenic mice; G. Lauvau (INSERM, University of Sofia Antipolis, Valbonne, France) for providing BALB/c TLR2−/− mice; S. Akira (Osaka University, Japan) and B. Ryffel (CNRS Orleans, France) for C57BL/6 Tlr1−/−, Tlr2−/−, Tlr3−/−, Tlr4−/− (ref. 44), Tlr5−/−, Tlr6−/−, Tlr7−/−, Tlr9−/−, Trif−/− and Myd88−/− mice; C. Théry (Institut Curie, Paris, France) for providing OVA-transfected TS/A cell and EL4 cells; E. Tartour (Hôpital Européen Georges-Pompidou, Assistance Publique–Hôpitaux de Paris, France) for providing B3Z and B09710 clones and A. Carpentier (Centre Hospitalier Universitaire Pitié Salpétrière, Paris, France) for providing CpG oligodeoxynucleotide 28. This work was supported by special grants from the Ligue contre le Cancer (G.K., L.Z.), Association pour le recherche contre le cancer (G.M.), Institut National contre le Cancer (L.Z., G.K.), Fondation pour la Recherche Médicale (G.K., L.Z., A.T.), Institut National de la Santé et de la Recherche Médicale (F.G.), Association for International Cancer Research (G.K., L.Z.) and European Union (DC-Thera, Allostem for L.Z., RIGHT for G.K.).

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L.A., F.G., A.T., M.O., G.M., M.C.M. and E.U. performed the in vivo and in vitro experiments. C.O. performed in vitro experiments. A.C. performed immunoprecipitations. B.R. provided transgenic mice. F.J.B., H.Y. and F.L. provided essential reagents. R.L., C.N., J.-P.M., A.C., V.J., F.C.-C., S.D. and T.T. recorded and provided the patients' data. L.A. and P. Saulnier performed patients' genotyping. A.T., F.A. and F.G. conducted data analysis. S.A. offered scientific advice and gave technical hints on the direction of the study. L.Z. and G.K. conceived the study and wrote the manuscript. P. Saftig provided the LAMP2−/− mice. J.B. set up the radiotherapy protocols in vivo.

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Correspondence to Guido Kroemer or Laurence Zitvogel.

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Apetoh, L., Ghiringhelli, F., Tesniere, A. et al. Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13, 1050–1059 (2007). https://doi.org/10.1038/nm1622

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