Fas ligand on tumor cells mediates inactivation of neutrophils.

The expression of Fas ligand (FasL) on tumor cells (tumor FasL) has been implicated in their evasion of immune surveillance. In this study, we investigated the cellular mechanism for FasL-associated immune escape using melanoma B16F10-derived cells as a model. Transfectants carrying FasL-specific ribozymes expressed low levels of FasL (FasL(low) tumor cells) as compared with those carrying enhanced green fluorescent protein-N1 plasmids (FasL(high) tumor cells). When injected s.c. into C57BL/6 mice, FasL(low) tumor cells grew more slowly than did FasL(high) melanoma cells. FasL(high) tumor cells showed more intensive neutrophilic infiltration accompanied by multiple necrotizing areas than did FasL(low) tumor cells. The average size of FasL(low) tumors, but not of FasL(high) tumors, was significantly enhanced in mice depleted of neutrophils. Consistently, a local injection of LPS to recruit/activate neutrophils significantly delayed tumor formation by FasL(low) tumor cells, and slightly retarded that of FasL(high) tumor cells in both C57BL/6 and nonobese diabetic/SCID mice. Neutrophils killed FasL(low) melanoma cells more effectively than FasL(high) melanoma cells in vitro. The resistance of FasL(high) melanoma cells to being killed by neutrophils was correlated with impaired neutrophil activation, as demonstrated by reductions in gelatinase B secretion, reactive oxygen species production, and the surface expression of CD11b and the transcription of FasL. Local transfer of casein-enriched or PMA-treated neutrophils delayed tumor formation by melanoma cells. Taken together, inactivation of neutrophils by tumor FasL is an important mechanism by which tumor cells escape immune attack.