PMID- 16688182 OWN - NLM STAT- MEDLINE DCOM- 20060816 LR - 20220408 IS - 1476-4687 (Electronic) IS - 0028-0836 (Linking) VI - 442 IP - 7101 DP - 2006 Jul 27 TI - IL-23 promotes tumour incidence and growth. PG - 461-5 AB - Chronic inflammation has long been associated with increased incidence of malignancy and similarities in the regulatory mechanisms have been suggested for more than a century. 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 inflammation. 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 cancer. 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 hurdle. 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. FAU - Langowski, John L AU - Langowski JL AD - Schering-Plough BioPharma, 901 California Avenue, Palo Alto, California 94304, USA. FAU - Zhang, Xueqing AU - Zhang X FAU - Wu, Lingling AU - Wu L FAU - Mattson, Jeanine D AU - Mattson JD FAU - Chen, Taiying AU - Chen T FAU - Smith, Kathy AU - Smith K FAU - Basham, Beth AU - Basham B FAU - McClanahan, Terrill AU - McClanahan T FAU - Kastelein, Robert A AU - Kastelein RA FAU - Oft, Martin AU - Oft M LA - eng PT - Journal Article DEP - 20060510 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (IL23A protein, human) RN - 0 (Il23a protein, mouse) RN - 0 (Interleukin-23) RN - 0 (Interleukin-23 Subunit p19) RN - 0 (Interleukins) RN - 187348-17-0 (Interleukin-12) SB - IM MH - Animals MH - CD8-Positive T-Lymphocytes/immunology MH - Cell Division MH - Genetic Predisposition to Disease MH - Humans MH - Inflammation/genetics/pathology MH - Interleukin-12/biosynthesis/immunology MH - Interleukin-23 MH - Interleukin-23 Subunit p19 MH - Interleukins/biosynthesis/deficiency/genetics/*metabolism MH - Mice MH - Mice, Inbred C57BL MH - Neoplasms/genetics/immunology/*metabolism/*pathology MH - Signal Transduction EDAT- 2006/05/12 09:00 MHDA- 2006/08/17 09:00 CRDT- 2006/05/12 09:00 PHST- 2005/11/22 00:00 [received] PHST- 2006/04/11 00:00 [accepted] PHST- 2006/05/12 09:00 [pubmed] PHST- 2006/08/17 09:00 [medline] PHST- 2006/05/12 09:00 [entrez] AID - nature04808 [pii] AID - 10.1038/nature04808 [doi] PST - ppublish SO - Nature. 2006 Jul 27;442(7101):461-5. doi: 10.1038/nature04808. Epub 2006 May 10.