Depletion of the Natural Killer Cell Population in the Peritoneum by AK-5 Tumor Cells Overexpressing Fas-Ligand: A Mechanism of Immune Evasion

Abstract

AK-5 tumor kills 100% hosts when injected ip and only 20–30% of animals die when the tumor cells are transplanted sc. Seventy percent of animals regress the subcutaneous tumor and exhibit total immunity against subsequent challenges of AK-5 cells by either route. Initially the 100% killing in ip-injected animals was attributed to the rapid growth of the tumor cells in the peritoneum thereby not giving enough time for the host immune system to mount an antitumor response. In the present report we have demonstrated overexpression of Fas-L by day 3 and day 4 ascitic tumor cells which depletes the peritoneum of Fas+lymphocytes. In addition the effector cells from the ascites are ineffective in inducing cytotoxicity against tumor cellsin vitro.However, splenocytes from animals bearing ip tumors possessed cytotoxicity against YAC-1 as well as AK-5 cells. We have also shown the presence of soluble Fas-L in the ascitic fluid, which induced DNA fragmentation in Fas+Jurkat cells. Fas-L present in the tumor cells is able to induce apoptosis in activated lymphocytes and Jurkat cells, suggesting retention of its biological function. These studies implicate Fas-L in the depletion of the effector cell number and inhibition of their functional activity. They also suggest differential regulation of Fas-L expression by the tumor cells depending upon the site of transplantation.