INVOLVEMENT OF LIVER-ASSOCIATED IMMUNITY IN HEPATIC METASTASIS FORMATION

Aims. Hepatic metastasis formation and prevention were studied from th e viewpoint of liver-associated immunity. Methods. RCN-9, a colonic ca ncer cell line derived from Fischer rats, and its subclone RCN-H4, in which the cancer is highly metastatic to the liver, were used. Fischer rats that were inoculated with parent RCN-9 colonic cancer cells (5 x 10(6)) via the portal vein showed liver metastasis in less than 60% o f the animals. In contrast, all rats (100%) that received RCN-H4 produ ced multiple liver metastases. To investigate the difference of hepati c metastasis formation, we assessed the susceptibility of both cell li nes against hepatic sinusoidal lymphocytes (HSL) by Cr-51-release assa y, and the expression of MHC class I and class II of both cell lines b y flow cytometry. In addition, we examined whether activation of HSL b y interleukin-12 (IL-12) can prevent liver metastasis of highly metast atic clone RCN-H4. Results. The RCN-H4 clone showed decreased suscepti bility to lysis by natural cytotoxic cells in HSL. This decrease in su sceptibility was attributable to an increase in cell surface expressio n of MHC class I antigen. Administration of IL-12, a potent NK/CTL sti mulatory cytokine, augmented the cytotoxic activity against the RCN-H4 clone and prevented liver metastasis of RCN-H4 inoculated into the po rtal vein. Conclusions. Liver metastasis formation is positively corre lated with the strength of the hepatic immune system which mainly cons ists of ontogenetically primitive T cells. As these effecters exert th eir cytotoxicity in a MHC-nonrestricted fashion, tumor cells that high ly express MHC class I antigen can readily avoid hepatic surveillance and apt to cause liver metastasis. Augmentation of the hepatic immune system, for instance, with IL-12 administration, can prevent liver met astasis even in tumor cells with a high potential for liver metastasis . (C) 1998 Academic Press.