Resistance of tumor cells to tumor necrosis factor.

TNF-alpha is clearly an important mediator of in vitro tumor cell cytotoxicity induced by the activated macrophage. There are a number of other nonspecific mediators of tumor cell cytotoxicity. These include natural killer cells (51, 52), lymphokine-activated killer cells (53), and natural cytotoxic cells (54). The role that TNF-alpha may play in the cytotoxicity induced by these cell types has not been completely elucidated. Neither is it known what role, if any, TNF-alpha may play in major histocompatibility-restricted (T cell)-mediated tumor cell cytotoxicity. Just as in the case of the activated macrophage, activated cytotoxic T cells produce a number of mediators that inhibit the growth of tumor cells or that induce tumor cell cytotoxicity (55). The role that TNF-alpha plays in the whole process of the regulation of tumorigenesis will not become completely defined until an appropriate set of genetic experiments is completed which utilizes transplantable tumor cell lines selected specifically for resistance to this cytokine in in vivo tumor models. The prominance of TNF-alpha as a mediator of macrophage-induced tumor cell cytotoxicity makes it a candidate for analysis in studies of the early stages of tumorigenesis. We have chosen to study mechanisms of resistance to this monokine. Our results have shown that there are multiple pathways leading to resistance to TNF-alpha-induced tumor cell cytotoxicity. These pathways include the production of transforming growth factors by tumor cells and the amplified expression of certain oncogenes. Other pathways will undoubtedly become elucidated as we begin to define the molecular mechanisms giving rise to the resistant phenotype.