Abstract
The potent tumoricidal activity of interleukin 12 (IL-12) is thought to be mediated by the activation and polarization of natural killer (NK) cells and T helper type 1 (TH1) cells, respectively. By systematic analysis of the IL-12-induced immune response to subcutaneous melanoma (B16), we found that tumor suppression was mediated independently of T lymphocytes or NK cells. IL-12 initiated local antitumor immunity by stimulating a subset of NKp46+ lymphoid tissue–inducer (LTi) cells dependent on the transcription factor RORγt. The presence of these NKp46+ LTi cells induced upregulation of adhesion molecules in the tumor vasculature and resulted in more leukocyte invasion. Thus, this innate cell type is responsive to IL-12 and is a powerful mediator of tumor suppression.
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Acknowledgements
We thank S. Bulfone-Paus (Research Center Borstel) for Il15ra−/− mice; A. Diefenbach (University Hospital Freiburg) for Rorc-eYFP mice; Y. Iwakura (University of Tokyo) for Il17a−/− mice; J.C. Renauld (Ludwig Institute Brussels) for Il22−/− mice; R. Zinkernagel (University Hospital of Zurich) for anti-CD4 and anti-CD8; M. Kopf and A. Diefenbach for discussions; and V. Tosevski, S. Burkhard, B. Sobotka, V. Wortmann and S. Behnke for technical assistance. Supported by the Swiss National Science Foundation (B.B.), the Swiss Cancer League (B.B.), the Center for Neurosciences Zurich (M.E.) and the Marie Heim-Vögtlin Programme (E.S.).
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M.E. and E.S. designed and did the experiments and analyzed the data; J.v.B. did experiments and analyzed the histology; G.K. provided advice for the histological analysis; B.B. designed the experiments, supervised and funded the study; B.B. and M.E. wrote the report.
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Eisenring, M., vom Berg, J., Kristiansen, G. et al. IL-12 initiates tumor rejection via lymphoid tissue–inducer cells bearing the natural cytotoxicity receptor NKp46. Nat Immunol 11, 1030–1038 (2010). https://doi.org/10.1038/ni.1947
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DOI: https://doi.org/10.1038/ni.1947
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