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An interleukin-17–mediated paracrine network promotes tumor resistance to anti-angiogenic therapy

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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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Figure 1: The role of soluble factors in mediating resistance to antibodies to VEGF and identification of IL-17 as the most abundant cytokine in a refractory tumor type.
Figure 2: Paracrine IL-17 function is required for refractoriness to treatment with antibodies to VEGF.
Figure 3: IL-17 signaling is required for the mobilization and tumor infiltration of CD11b+Gr1+ cells.
Figure 4: IL-17 signaling regulates the function of immature myeloid CD11b+Gr1+ cells from tumor-bearing mice and promotes tumor angiogenesis.
Figure 5: IL-17 induction of proinflammatory cytokines in tumor-associated fibroblasts is dependent on the activity of NF-κB and MEK1/2.
Figure 6: TH17 cells mediate resistance to treatment with antibodies to VEGF through the recruitment to and activation of CD11b+Gr1+ cells in the tumor microenvironment.

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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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