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*
Intramural Research Support Program, Science Applications International Corporation-Frederick,
Laboratory of Experimental Immunology, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, and
Department of Experimental Transplantation and Immunology, Division of Clinical Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702; and
§
Pediatric Oncology Branch, DCS, National Cancer Institute, Bethesda, MD 20892
Mice bearing the experimental murine renal cancer Renca can be
successfully treated with some forms of immunotherapy. In the present
study, we have investigated the molecular pathways used by NK and T
cells to lyse Renca cells. Renca cells normally express low levels of
Fas that can be substantially enhanced by either IFN-
or TNF-
,
and the combination of IFN- + TNF- synergistically enhances
cell-surface Fas expression. In addition, cells pretreated with IFN-
and TNF- are sensitive to lysis mediated by Fas ligand
(FasL)-expressing hybridomas (dllS), cross-linking of anti-Fas Abs
or soluble Fas (FasL). Lysis via Fas occurs by apoptosis, since Renca
shows all the typical characteristics of apoptosis. No changes in
levels of bcl-2 were observed after cytokine treatments. We also
examined cell-mediated cytotoxic effects using activated NK cells and T
cells from gld FasL-deficient mice, and perforin-deficient
mice, as well as wild-type C57BL/6 and BALB/c mice. Interestingly, the
granule-mediated pathway predominated in killing of Renca by activated
NK cells, while the Fas/FasL pathway contributed significantly to
cell-mediated killing of Renca by activated T cells. These results
suggest that killing of Renca tumor cells by immune effector cells can
occur by both granule and Fas-mediated cytotoxicity. However, for the
Fas-mediated pathway to function, cell surface levels of Fas need to be
increased beyond a critical threshold level by proinflammatory
cytokines such as IFN- and TNF-.
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