Letter

Nature advance online publication 10 May 2006 | = doi:10.1038/nature04808; = Received 22=20 November 2005; Accepted 11 April 2006; Published online 10 May 2006

IL-23 promotes tumour incidence and growth

John L. Langowski^1,2,=20 Xueqing Zhang^1,2,=20 Lingling Wu¹,=20 Jeanine D. Mattson¹,=20 Taiying Chen¹,=20 Kathy Smith¹,=20 Beth Basham¹,=20 Terrill McClanahan¹,=20 Robert A. Kastelein¹=20 and Martin Oft¹

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Chronic inflammation has long been associated with = increased=20 incidence of malignancy and similarities in the regulatory mechanisms = have been=20 suggested for more than a century¹. Infiltration of innate = immune=20 cells, elevated activities of matrix metalloproteases and increased = angiogenesis=20 and vasculature density are a few examples of the similarities between = chronic=20 and tumour-associated inflammation². Conversely, the = elimination of=20 early malignant lesions by immune surveillance, which relies on the = cytotoxic=20 activity of tumour-infiltrating T cells or intra-epithelial lymphocytes, = is=20 thought to be rate-limiting for the risk to develop cancer³. = Here we=20 show a molecular connection between the rise in tumour-associated = inflammation=20 and a lack of tumour immune surveillance. Expression of the = heterodimeric=20 cytokine interleukin (IL)-23, but not of its close relative IL-12, is = increased=20 in human tumours. Expression of these cytokines antagonistically = regulates local=20 inflammatory responses in the tumour microenvironment and infiltration = of=20 intra-epithelial lymphocytes. Whereas IL-12 promotes infiltration of = cytotoxic T=20 cells, IL-23 promotes inflammatory responses such as upregulation of the = matrix=20 metalloprotease MMP9, and increases angiogenesis but reduces CD8 T-cell=20 infiltration. Genetic deletion or antibody-mediated elimination of IL-23 = leads=20 to increased infiltration of cytotoxic T cells into the transformed = tissue,=20 rendering a protective effect against chemically induced carcinogenesis. = Finally, transplanted tumours are growth-restricted in hosts depleted = for IL-23=20 or in IL-23-receptor-deficient mice. Although many strategies for immune = therapy=20 of cancer attempt to stimulate an immune response against solid tumours, = infiltration of effector cells into the tumour tissue often appears to = be a=20 critical hurdle^4,^5,^6,⁷. = We show=20 that IL-23 is an important molecular link between tumour-promoting=20 pro-inflammatory processes and the failure of the adaptive immune = surveillance=20 to infiltrate tumours.

Schering-Plough BioPharma (formerly DNAX Research, Inc.), = 901=20 California Avenue, Palo Alto, California 94304, USA=20
*These authors contributed equally to this work

Correspondence to: Martin Oft¹=20 Correspondence and requests for materials should be addressed to M.O.=20 (Email: martin.oft@spcorp.com).

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IL-23 promotes tumour incidence and growth

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