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IL-23 promotes tumour incidence and growth

Abstract

Chronic inflammation has long been associated with increased incidence of malignancy and similarities in the regulatory mechanisms have been suggested for more than a century1. Infiltration of innate immune cells, elevated activities of matrix metalloproteases and increased angiogenesis and vasculature density are a few examples of the similarities between chronic and tumour-associated inflammation2. Conversely, the elimination of early malignant lesions by immune surveillance, which relies on the cytotoxic activity of tumour-infiltrating T cells or intra-epithelial lymphocytes, is thought to be rate-limiting for the risk to develop cancer3. Here we show a molecular connection between the rise in tumour-associated inflammation and a lack of tumour immune surveillance. Expression of the heterodimeric cytokine interleukin (IL)-23, but not of its close relative IL-12, is increased in human tumours. Expression of these cytokines antagonistically regulates local inflammatory responses in the tumour microenvironment and infiltration of intra-epithelial lymphocytes. Whereas IL-12 promotes infiltration of cytotoxic T cells, IL-23 promotes inflammatory responses such as upregulation of the matrix metalloprotease MMP9, and increases angiogenesis but reduces CD8 T-cell infiltration. Genetic deletion or antibody-mediated elimination of IL-23 leads to increased infiltration of cytotoxic T cells into the transformed tissue, rendering a protective effect against chemically induced carcinogenesis. Finally, transplanted tumours are growth-restricted in hosts depleted for IL-23 or in IL-23-receptor-deficient mice. Although many strategies for immune therapy of cancer attempt to stimulate an immune response against solid tumours, infiltration of effector cells into the tumour tissue often appears to be a critical hurdle4,5,6,7. We show that IL-23 is an important molecular link between tumour-promoting pro-inflammatory processes and the failure of the adaptive immune surveillance to infiltrate tumours.

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Figure 1: Overexpression of IL-23 but not of IL-12 in human cancer.
Figure 2: Tumour resistance with reduced inflammation in IL-23-deficient animals.
Figure 3: IL-12 stimulates, but IL-23 decreases, immune surveillance by CD8 T cells.
Figure 4: Functional ablation of IL-23p19 signalling restricts tumour growth.

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Acknowledgements

We thank C. Strader for her comments on the manuscript. Author Contributions J.L.L. and X.Z. contributed equally to this work.

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Correspondence to Martin Oft.

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Langowski, J., Zhang, X., Wu, L. et al. IL-23 promotes tumour incidence and growth. Nature 442, 461–465 (2006). https://doi.org/10.1038/nature04808

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