ABNORMAL SIGNAL-TRANSDUCTION BY T-CELLS OF MICE WITH PARENTAL TUMORS IS NOT SEEN IN MICE BEARING IL-2-SECRETING TUMORS

There is considerable evidence to demonstrate that immune function is abnormal in tumor-bearing mice, perhaps accounting, at least in part, for progressive tumor growth. In an attempt to generate an antitumor r esponse, we used retroviral vectors to express IL-2 cDNA in CMS5, a mu rine fibrosarcoma. Mice inoculated with unmodified tumor cells suffere d progressive tumor growth, whereas tumors secreting IL-2 were rejecte d or grew slowly. Animals bearing unmodified but not IL-2-secreting tu mors also were immunosuppressed. On the basis of these observations, w e were interested in how IL-2 secretion by the tumor cells prevented t he onset of hyporesponsiveness. To identify biochemical differences be tween T cells of mice with parental vs slowly growing IL-2-secreting t umors, we examined signal transduction after activation through the CD 3/TCR complex. Protein tyrosine phosphorylation was altered and calciu m flux was reduced in cells of mice with parental tumors compared with animals with slowly growing IL-2-secreting tumors. In addition, level s of protein for the tyrosine kinases p56(lck) and p59(fyn), as well a s the TCR-zeta-chain, were reduced. These differences in signal transd uction were observed for T cells of mice with parental and IL-2-secret ing tumors of the same size, demonstrating that differences in tumor s ize alone could not explain our findings. Thus, IL-2 secretion by tumo rs seems to be able to prevent immunosuppression by maintaining normal signal transduction in T cells, facilitating the generation of antitu mor responses.