Cholangiocarcinomas express Fas ligand and disable the Fas receptor

Cholangiocarcinoma is a highly-malignant adenocarcinoma originating from ch olangiocytes. Current concepts support escape from immune surveillance usin g aberrant expression of Fas ligand (FasL) and dysregulation of receptor (F asR) signaling as a potential mechanism for tumor progression. Our aims wer e to determine if altered expression of FasR and Fast or changes in express ion of FLICE inhibitor (I-FLICE) allow cholangiocarcinoma cells to escape i mmune surveillance. Human cholangiocarcinoma cell lines were evaluated for the functional expression of FasR and Fast by (1) quantitating apoptosis af ter incubation of cells with agonistic antibodies and (2) an in vitro cell death assay involving coculture of cholangiocarcinoma cells with Fas-sensit ive thymocytes. I-FLICE antisense treatment was performed by stable transfe ction with complementary DNA (cDNA) for I-FLICE in the reverse orientation. We found that normal cholangiocytes in vivo express Fast. Human cholangioc arcinoma cell lines express both Fast and FasR and I-FLICE, Fast expressed by cholangiocarcinomas in vitro induced lymphocyte cell death (70% after 24 hours). Despite the expression of FasR, exposure of the cells to agonistic antibodies (500 ng/mL) induced only minimal apoptosis in the Jurkat cells. Antisense treatment of cholangiocarcinomas in vitro with I-FLICE reduced p rotein expression of I-FLICE by 90% to 95% and increased Fas-mediated apopt osis 2-fold. We concluded that cholangiocarcinomas escape immune surveillan ce either by disabling FasR signaling through the expression of I-FLICE and /or increased Fast expression to induce apoptosis of invading T cells. Redu ction of I-FLICE expression in cholangiocarcinoma cells restored Fas-mediat ed apoptosis. Therapeutic maneuvers to inhibit expression of I-FLICE may ai d in the treatment of cholangiocarcinoma.