Abstract
The interferon (IFN)-γ–induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice1,2. Here we show that the main source of IFN-γ is not the conventional NK cell but a subset of B220+Ly6C− dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220+NK1.1+ dendritic cells secrete high levels of IFN-γ and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2−/−Il2rg−/− mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response.
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References
Smyth, M.J. et al. Nature's TRAIL—on a path to cancer immunotherapy. Immunity 18, 1–6 (2003).
Yagita, H., Takeda, K., Hayakawa, Y., Smyth, M.J. & Okumura, K. TRAIL and its receptors as targets for cancer therapy. Cancer Sci. 95, 777–783 (2004).
Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).
Kaplan, D.H. et al. Demonstration of an IFNγ-dependent tumor surveillance system in immunocompetent mice. Proc. Natl. Acad. Sci. USA 95, 7556–7561 (1998).
Diefenbach, A., Jensen, E.R., Jamieson, A.M. & Raulet, D.H. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413, 165–171 (2001).
Glas, R., Ohlen, C., Hoglund, P. & Karre, K. The CD8+ T cell repertoire in beta 2-microglobulin-deficient mice is biased towards reactivity against self-major histocompatibility class I. J. Exp. Med. 179, 661–672 (1994).
Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002).
Smyth, M.J. et al. NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer. J. Exp. Med. 200, 1325–1335 (2004).
Borg, C. et al. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J. Clin. Invest. 114, 379–388 (2004).
Smyth, M.J. et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J. Exp. Med. 193, 661–670 (2001).
Shin, E.C. et al. IFN-gamma induces cell death in human hepatoma cells through a TRAIL/death receptor-mediated apoptotic pathway. Int. J. Cancer 93, 262–268 (2001).
Pelayo, R. et al. Derivation of two categories of plasmacytoid dendritic cells in murine bone marrow. Blood 105, 4407–4415 (2005).
Chan, C.W. et al. IFN producing Killer-dendritic cells directly link innate and adaptative immunity. Nat. Med. (in the press).
Durali, D. et al. In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment. Blood 102, 4084–4089 (2003).
Munder, M., Mallo, M., Eichmann, K. & Modolell, M. Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: A novel pathway of autocrine macrophage activation. J. Exp. Med. 187, 2103–2108 (1998).
Fukao, T., Matsuda, S. & Koyasu, S. Synergistic effects of IL-4 and IL-18 on IL-12-dependent IFN-gamma production by dendritic cells. J. Immunol. 164, 64–71 (2000).
Ohteki, T. et al. Interleukin 12-dependent interferon gamma production by CD8alpha+ lymphoid dendritic cells. J. Exp. Med. 189, 1981–1986 (1999).
Trinite, B., Voisine, C., Yagita, H. & Josien, R. A subset of cytolytic dendritic cells in rat. J. Immunol. 165, 4202–4208 (2000).
Homann, D. et al. CD40L blockade prevents autoimmune diabetes by induction of bitypic NK/DC regulatory cells. Immunity 16, 403–415 (2002).
Hochrein, H. et al. Differential production of IL-12, IFN-alpha, and IFN-gamma by mouse dendritic cell subsets. J. Immunol. 166, 5448–5455 (2001).
Vidalain, P.O. et al. Measles virus induces functional TRAIL production by human dendritic cells. J. Virol. 74, 556–559 (2000).
Wang, H. et al. Imatinib mesylate (STI-571) enhances antigen-presenting cell function and overcomes tumor-induced CD4+ T-cell tolerance. Blood 105, 1135–1143 (2005).
Mohty, M. et al. Imatinib and plasmacytoid dendritic cell function in patients with chronic myeloid leukemia. Blood 103, 4666–4668 (2004).
Ray, C.A. et al. Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme. Cell 69, 597–604 (1992).
Schneider, P. et al. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 7, 831–836 (1997).
Bonnotte, B. et al. Identification of tumor-infiltrating macrophages as the killers of tumor cells after immunization in a rat model system. J. Immunol. 167, 5077–5083 (2001).
Acknowledgements
We thank F. Housseau for communicating his data on IKDCs and providing reagents, J. Tschopp (University of Lausanne) and G. Salvesen (Burnham Institute) for providing plasmids and M.L. Albert (Pasteur Institute) for providing reagents. J. Taieb is supported by a Poste d'accueil INSERM and AP-HP, and N. Chaput is supported by a European fellowship (QLRT-2001-00093) and by the Association for Research Against Cancer (ARC). E. Ullrich was supported by the Deutsche Forschungsgemeinschaft and M. Bonmort by the Poste d' Accueil INSERM. This work was also supported by EU grants (ALLOSTEM, DC THERA), ARC and the Ligue Nationale contre le Cancer (équipes labelisées de G.K. and L.Z).
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Supplementary information
Supplementary Fig. 1
Regressing tumors are invaded by CD11c+B220+Gr1− cells. (PDF 380 kb)
Supplementary Fig. 2
Phenotypic analyses of B220+NK1.1+ DCs in spleens of naive mice. (PDF 37 kb)
Supplementary Fig. 3
Localization of IKDCs in vivo. (PDF 31 kb)
Supplementary Fig. 4
The IFN-γ receptor is crucial for the antitumor effects mediated by imatinib mesylate +IL-2. (PDF 27 kb)
Supplementary Fig. 5
IKDCs are functional in Rag2−/−Il2rg−/− mice. (PDF 28 kb)
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Taieb, J., Chaput, N., Ménard, C. et al. A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med 12, 214–219 (2006). https://doi.org/10.1038/nm1356
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DOI: https://doi.org/10.1038/nm1356
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