282. Effects of Fas Ligand on Inflammation and Tumor Survival Are Dependent on Its Expression Levels

Abstract

The Fas ligand (FasL) is expressed in a variety of human carcers and has been implicated in tumor evasion by inducing apoptosis of activated Fas-positive cytotoxic T cells. Experimental studies however demonstrated that ectopic expression of FasL in muirne tumors triggered neutrophils-mediated inflammatory responses and subsequently produces tumor rejection. To understand the mechanism of these conflicting observations, we established murine melanoma and lung carcinoma lines expressing different levels of FasL and examined their tumorigenicity in syngeneic mice. Expression of FasL on tumors was determined by in vitro cytotoxicity to Fas-positive cell. Tumors with a high level of FasL were rapidly rejected in immunocompetent mice, while those expressing a low level of FasL were not rejected and grew faster than FasL-negative parental tumors. The growth enhancement of FasL-low tumors was not observed in T cell-defective nude mice, suggesting that FasL expressed on tumors at a low level counteracted against T cell-dependent antitumor responses. In support of this notion, growth of FasL-low tumors was greater than that of parental tumors in the mice that had developed tumor-specific immunity. Histological examinations revealed that infiltration of neutrophils depended on the expression level of FasL and that apoptosis of lymphocytes was detected in the vicinity of FasL-low tumors. These results suggest that FasL on tumors has dual function, antitumor effects and tumor evasion, which are determined by its expression level.