growth or by activating cellular immunity. The cytostatic effects of tumor necrosis factor-a 
(TNF-a) (23) and lymphotoxin (24) can result in neoplastic cell death. Interferon- (IFN-_) 
markedly increases class I MHC cell surface expression (25,26) and synergizes with TNF-_ 
in producing this effect (27). Colony stimulating factors such as G-CSF and GM-CSF 
activate neutrophils and macrophages to lyse tumor cells directly (28), and interleukin-2 
(IL-2) activates Leu-19+ NK cells to generate lymphokine activated killer cells (LAK) 
capable of lysing autologous, syngeneic or allogeneic tumor cells but not normal cells 
(17,29,30). The LAK cells lyse tumor cells without preimmunization or MHC restriction 
(31). Interleukin-4 (IL-4) also generates LAK cells and acts synergistically with IL-2 in the 
generation of tumor specific killer cells (32). 
Since most malignancies arise in immunocompetent hosts, it is likely that tumor cells have 
evolved mechanism to escape host defenses, perhaps through evolution of successively less 
immunogenic clones (33). Deficient expression of class I MHC molecules limits the ability 
of tumor cells to present antigens to cytotoxic T cells. Freshly isolated cells from naturally 
occurring tumors frequently lack class I MHC antigen completely or show decreased 
expression (34-38). Reduced class I MHC expression could also facilitate growth of these 
tumors when transplanted into syngeneic recipients. Several tumor cell lines which exhibit 
low levels of class I MHC proteins become less oncogenic when expression vectors 
encoding the relevant class I MHC antigen are introduced into them (39-43). In some 
experiments, tumor cells which express a class I MHC gene confer immunity in naive 
recipients against the parental tumor (40,41). The absolute level of class I MHC expression 
however, is not the only factor which influences the tumorigenicity or immunogenicity of 
tumor cells. In one study, mouse mammary adenocarcinoma cells, treated with 5- 
azacytidine and selected for elevated levels of class I MHC expression did not display 
altered tumorigenicity compared to the parent line (44). 
The immune response to tumor cells can be stimulated by systemic administration of IL-2 
(45), or IL-2 with LAK cells (46,47). Clinical trials using tumor infiltrating lymphocytes are 
also in progress (48). Recently, several studies have examined the tumor suppressive effect 
of lymphokine production by genetically altered tumor cells. The introduction of tumor 
cells transfected with an IL-2 expression vector into syngeneic mice stimulated an MHC 
class I restricted cytolytic T lymphocyte response which protected against subsequent 
rechallenge with the parental tumor cell line (49). Expression of IL-4 by plasmacytoma or 
mammary adenocarcinoma cells induced a potent anti-tumor effect mediated by infiltration 
of eosinophils and macrophages (50). These studies demonstrate that cytokines, expressed 
at high local concentrations, are effective anti-tumor agents. 
Nabel and co-workers have previously proposed an alternative approach to stimulate an 
anti-tumor response, through the introduction of an allogeneic class I MHC gene into 
established human tumors. The antigenicity of tumor cells has been altered previously by 
the expression of viral antigens through infection of tumor cells (51-55), or expression of 
allogeneic antigens introduced by somatic cell hybridization (56,57). Allogeneic class I 
MHC genes have been introduced into tumor cells by transfection and subsequent selection 
in vitro. These experiments have produced some conflicting results. In one case, 
transfection of an allogeneic class I MHC gene (H-2L<^) into an H-2^ tumor resulted in 
Recombinant DNA Research, Volume 19 
[ 211 ] 
