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Laboratory of Tumor Immunology and Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
We have previously identified mutated ras peptides
reflecting the glycine to valine substitution at position 12 as
HLA-A2-restricted, CD8+ CTL neo-epitopes. CTL lines
produced against these peptide epitopes lysed the HLA-A2+
Ag-bearing SW480 primary colon adenocarcinoma cell line, although
IFN-
treatment of the targets was necessary to achieve efficient
cytotoxicity. Here, we compared the lytic phenotype of the SW480 cell
line to its metastatic derivative, SW620, as an in vitro paradigm to
further characterize the nature of a HLA class I-restricted,
Ag-specific CTL response against neoplastic cell lines of primary and
metastatic origin. Although both colon carcinoma cell lines were lysed
by these Ag-specific CTL following IFN- pretreatment, the mechanisms
of lysis were distinct, which reflected differential levels of
sensitivity to the Fas pathway. Whereas IFN- pretreatment rendered
SW480 cells sensitive to both Fas-dependent and -independent (perforin)
pathways, SW620 cells displayed lytic susceptibility to Fas-independent
mechanisms only. Moreover, pretreatment of SW480 cells with the
anti-colon cancer agent, 5-fluorouracil (5-FU), led to enhanced Fas
and ICAM-1 expression and triggered Ag-specific CTL-mediated lysis via
Fas- and perforin-based pathways. In contrast, these
phenotypic and functional responses were not observed with SW620 cells.
Overall, these data suggested that 1) IFN- and 5-FU may
enhance the lytic sensitivity of responsive colon carcinoma cells to
immune effector mechanisms, including Fas-induced lysis; 2) the
malignant phenotype may associate with resistance to Fas-mediated lysis
in response to Ag-specific T cell attack; and 3) if Ag-specific CTL
possess diverse lytic capabilities, this may overcome, to some extent,
the potential "escape" of Fas-resistant carcinoma
cells.
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