ROLE OF SPONTANEOUS AND INTERLEUKIN-2-INDUCED NATURAL-KILLER-CELL ACTIVITY IN THE CYTOTOXICITY AND REJECTION OF FAS(-) TUMOR-CELLS() AND FAS()

In the current study, we investigated whether the naive, poly I:C or i nterleukin-2 (IL-2)-induced natural killer (NK)/lymphokine-activated k iller (LAK) cells use perforin and/or pas ligand (FasL) to mediated cy totoxicity. We correlated these findings with the ability of mice to r eject syngeneic Fas(+) and Fas(-) tumor cells either spontaneously or after IL-2 treatment. The spontaneous NK-cell-mediated cytotoxicity wa s primarily perforin based, whereas the poly I:C and IL-2-induced NK/L AK activity was both FasL and perforin dependent. L1210 Fas(+) tumor t argets were more sensitive than L1210 Fas(-) targets to poly I:C and I L-2-induced cytotoxicity in wild-type, gld/gld, and perforin knockout mice. When L1210 Fas(+) and Fas(-) tumor cells were injected subcutane ously (sc) or intraperitoneally into syngeneic mice, Fas(-) tumor cell s caused mortality earlier than Fas(+) tumor cells. Also, approximatel y 20% of the mice injected sc with L1210 Fas(-) tumor cells survived t he challenge(>60 days), whereas all mice injected similarly with L1210 Fas(-) tumor cells died. When immunotherapy using IL-2 (10,000 U, thr ee times/d for a week, followed by once/d for an additional week) was attempted in mice injected sc with tumor cells, IL-2 treatment was ver y effective against mice bearing L1210 Fas(+) (40% survival) but not L 1210 Fas(-) (0% survival) tumors. These data correlated with the findi ng that the LAK cells from IL-2-injected mice caused increased cytotox icity against L1210 Fas(+) when compared with L1210 Fas(-) targets. Al so, L1210 Fas(+) tumor-bearing mice showed increased tumor-specific cy totoxic T lymphocyte (CTL) activity when compared with those bearing L 1210 Fas(-) tumor cells. Together our studies show for the first time that expression of pas on tumor targets makes them more immunogenic as well as susceptible to CTL- and IL-2-induced LAK activity. The Fas(+) tumor cells are also more responsive to immunotherapy with IL-2. (C) 1998 by The American Society of Hematology.