Abstract
Although angiogenesis inhibitors have provided substantial clinical benefit as cancer therapeutics, their use is limited by resistance to their therapeutic effects. While ample evidence indicates that such resistance can be influenced by the tumor microenvironment, the underlying mechanisms remain incompletely understood. Here, we have uncovered a paracrine signaling network between the adaptive and innate immune systems that is associated with resistance in multiple tumor models: lymphoma, lung and colon. Tumor-infiltrating T helper type 17 (TH17) cells and interleukin-17 (IL-17) induced the expression of granulocyte colony-stimulating factor (G-CSF) through nuclear factor κB (NF-κB) and extracellular-related kinase (ERK) signaling, leading to immature myeloid-cell mobilization and recruitment into the tumor microenvironment. The occurrence of TH17 cells and Bv8-positive granulocytes was also observed in clinical tumor specimens. Tumors resistant to treatment with antibodies to VEGF were rendered sensitive in IL-17 receptor (IL-17R)-knockout hosts deficient in TH17 effector function. Furthermore, pharmacological blockade of TH17 cell function sensitized resistant tumors to therapy with antibodies to VEGF. These findings indicate that IL-17 promotes tumor resistance to VEGF inhibition, suggesting that immunomodulatory strategies could improve the efficacy of anti-angiogenic therapy.
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Acknowledgements
We thank R. Khosla, I. Mellman, J. Kim, V. Phan, M. Yan and M. Junttila for helpful discussions and comments. We thank L. Komuves, C. Chalouni, M. Gonzales Edick and M. Sagolla for providing microscopy expertise and Genentech microarrays (in particular, Z. Modrusan), the Genentech animal and FACS facilities (in particular, A. Paler-Martinez) and D. Kallop and R. Weimer in animal imaging at Genentech. We thank N. Ota for help with Il17rc−/− mice.
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A.S.C. designed, planned and coordinated the experiments, analyzed the data and wrote the manuscript. N.F. coordinated and supervised the project and wrote the manuscript. A.S.C., X.W. and G.Z. performed the experiments. W.O. provided study design. Z.J. performed microarrays and bioinformatics analysis. H.N. and I.K. assisted with image acquisition and performed the analyses of clinical and preclinical samples, respectively. F.V.P. provided pathologist review and assessment of clinical samples. J.Z. and Y.G.M. performed mouse Bv8 ELISA. J.-M.V. and Y.G.M. performed intratumoral antibody ELISAs.
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A.S., X.W., G.Z., H.N., I.K., J.Z., J.-M.V., Z.J., Y.G.M., F.V., W.O. and N.F. are present or formers employees of Genentech/Roche.
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Chung, A., Wu, X., Zhuang, G. et al. An interleukin-17–mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med 19, 1114–1123 (2013). https://doi.org/10.1038/nm.3291
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DOI: https://doi.org/10.1038/nm.3291
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