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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4248-4255
Role of Spontaneous and Interleukin-2-Induced Natural Killer Cell
Activity in the Cytotoxicity and Rejection of Fas+
and Fas Tumor Cells
Mike Bradley,
Ahmet Zeytun,
Asimah Rafi-Janajreh,
Prakash S. Nagarkatti, and
Mitzi Nagarkatti
From the Department of Biology and the Department of Biomedical
Sciences & Pathobiology, Virginia-Maryland College of Veterinary
Medicine, Virginia Tech, Blacksburg, VA.
In the current study, we investigated whether the naive, poly I:C or
interleukin-2 (IL-2)-induced natural killer (NK)/lymphokine-activated killer (LAK) cells use perforin and/or Fas ligand
(FasL) to mediated cytotoxicity. We correlated these findings with the
ability of mice to reject syngeneic Fas+ and
Fas tumor cells either spontaneously or after IL-2
treatment. The spontaneous NK-cell-mediated cytotoxicity was primarily
perforin based, whereas the poly I:C and IL-2-induced NK/LAK activity
was both FasL and perforin dependent. L1210 Fas+ tumor
targets were more sensitive than L1210 Fas targets to
poly I:C and IL-2-induced cytotoxicity in wild-type, gld/gld,
and perforin knockout mice. When L1210 Fas+ and
Fas- tumor cells were injected subcutaneously (sc) or
intraperitoneally into syngeneic mice, Fas tumor cells
caused mortality earlier than Fas+ tumor cells. Also,
approximately 20% of the mice injected sc with L1210
Fas+ tumor cells survived the challenge(>60 days),
whereas all mice injected similarly with L1210 Fas tumor
cells died. When immunotherapy using IL-2 (10,000 U, three 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 very effective
against mice bearing L1210 Fas+ (40% survival) but not
L1210 Fas (0% survival) tumors. These data correlated
with the finding that the LAK cells from IL-2-injected mice caused
increased cytotoxicity against L1210 Fas+ when compared
with L1210 Fas targets. Also, L1210 Fas+
tumor-bearing mice showed increased tumor-specific cytotoxic T
lymphocyte (CTL) activity when compared with those bearing L1210 Fas tumor cells. Together our studies show for the first
time that expression of Fas 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.
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