Modulation of interleukin-18 expression in human colon carcinoma: Consequences for tumor immune surveillance

The production in colon cancer of interferon-gamma (IFN-gamma), a type-I T- helper (THI) cytokine, is considered as a marker of good prognosis. We aske d whether interleukin-18 (IL-18), which strongly induces IFN-gamma and regu lates Fas ligand (Fas-L)-dependent cytotoxicity, may play a role in colon h omeostasis, and if its expression was modulated in colon adenocarcinomas. W e analyzed 14 specimens of colon adenocarcinomas, 6 of normal colon mucosa of the series, and 6 colon-tumor cell lines. The expression of IL-18, of IC E protease, involved in the processing of this cytokine, and of the downstr eam effectors of IL-18, IFN-gamma and Fas-L was analyzed by RT-PCR. We furt her performed IL-18 immunostaining of normal and tumor specimens. The resul ts were correlated with tumor dissemination and clinical outcome. We report the synthesis of IL-18 in human normal colon, mainly by epithelial cells o f the mucosa. Out of the 6 tumor cell lines, 4 expressed IL-18 transcripts, but neither ICE mRNA nor secreted forms of IL-18 were detected. We observe d decreased or abolished synthesis of IL-18 in colon adenocarcinomas, as co mpared with normal mucosa, Thus, half of the colon-cancer tissues (7/14 cas es) expressed neither IFN-gamma nor Fas-L. This feature was correlated with the existence of distant metastases (Fischer's exact test, p = 0.02) and a n unfavorable outcome. These findings suggest that production of IL-18 in h uman colon may play a role in homeostasis and in tumor immune surveillance, by enhancing IFN-gamma production and Fas-L-dependent cytotoxicity of immu ne cells. Int J. Cancer (Pred. Oncol.) 84:326-330, 1999. (C) 1999 Wiley-Lis s. Inc.