Antitumor effects are produced by forced expression of membrane-bound but not soluble Fas ligand in murine lung carcinoma cells.

Interaction of Fas and Fas ligand (FasL) in immunocompetent cells plays a crucial role(s) in their effector functions and in the regulation of host immune responses. Expression of FasL in tumors possibly counteracts Fas-positive effector T cells that infiltrate into tumors and consequently the Fas/FasL interaction can contribute to the escape of tumor cells from systemic immune systems. However, forced expression of FasL in tumors unexpectedly induced migration of neutrophils into the tumors and the FasL-expressing tumors were rejected due to the inflammatory reaction. Since FasL is released from the cell surface, we examined whether soluble or membrane-bound FdsL molecules produced such antitumor effects. Fas-positive B cells were effectively killed by membrane-bound but not soluble FasL in which the leader sequence of interleukin-4 was ligated with the extracytoplasmic portion of FasL. Mice inoculated with A11 murine lung cancer cells expressing membrane-bound FasL did not develop tumors and had few spontaneous lung metastatic foci. In contrast, mice injected with A11 cells secreting soluble FasL developed tumors; the growth of the tumors and the number of lung metastatic foci from subcutaneous tumors were not different from those of parent tumors. The chemotactic activity of FasL, tested by intraperitoneal injection of parent and the FasL-expressing A11 cells, showed that the level of neutrophil migration by A11 cells secreting soluble FasL was greater than that by parent cells but was not as significant as that by A11 cells expressing membrane-bound FasL. The antitumor activity induced by expressed FasL seems to be correlated with the apoptosis-inducing activity through the Fas/FasL interaction but not directly with the chemotactic activity for neutrophils.