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Interleukin-22 promotes tumor angiogenesis

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Abstract

TH17 cells play important yet complex roles in cancer development and progression. We previously reported that TH17 cells and IL-17 mediate resistance to anti-VEGF therapy by inducing recruitment of immunosuppressive and proangiogenic myeloid cells to the tumor microenvironment. Here, we demonstrate that IL-22, a key effector cytokine expressed by TH17 cells, directly acts on endothelial cells to promote tumor angiogenesis. IL-22 induces endothelial cell proliferation, survival, and chemotaxis in vitro and neovascularization in an ex vivo mouse choroid explant model. Blockade of IL-22, with a neutralizing antibody, significantly inhibits tumor growth associated with reduced microvascular density. No synergistic effect of IL-22 with VEGF was observed. These results identify IL-22 as a potential therapeutic target for blocking tumor angiogenesis.

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Acknowledgements

We thank Genentech. Inc. for generously providing us with the anti-VEGF and anti-IL-22 antibodies for neutralization experiments. We thank Dr. Wenjun Ouyang (Amgen, Inc.) for helpful discussion and advice. We also thank Dr. Karen Messer and Yuqi Qin from the department of Biostatistics and Bioinformatics at Moores UCSD Cancer Center for help and advice with statistical analysis.

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Authors and Affiliations

  1. Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA

    Nicholas J. Protopsaltis, Wei Liang & Napoleone Ferrara

  2. Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA

    Eric Nudleman

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  1. Nicholas J. Protopsaltis
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Correspondence to Napoleone Ferrara.

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10456_2018_9658_MOESM1_ESM.pptx

Supplementary Fig. 1 Expression of IL-22 by EL4 cells. EL4 cells were treated with 1 ng/mL of TGFβ and 20 ng/mL IL-6 under normoxia and hypoxia (1% O2). IL-22 protein levels in the EL4 cell conditioned medium were determined by ELISA. Error bars indicate standard deviation, n = 3–7 replicates from 3 independent experiments. n.s. not significant, *p < 0.05. Supplementary material 1 (PPTX 587 KB)

10456_2018_9658_MOESM2_ESM.pptx

Supplementary Fig. 2 Anti-IL-22 does not Inhibit EL4 (a) or GL261 (b) cell growth in vitro. Cell viability was assessed by the Alamar blue assay and fluorescence readings at 590 nm (excited at 530 nm) were used as readouts. Error bars indicate standard deviation. Data from three experiments were pooled for a total number of 5–8 replicates per experimental condition. n.s. not significant. Supplementary material 2 (PPTX 1274 KB)

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Protopsaltis, N.J., Liang, W., Nudleman, E. et al. Interleukin-22 promotes tumor angiogenesis. Angiogenesis 22, 311–323 (2019). https://doi.org/10.1007/s10456-018-9658-x

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