MOLECULAR-BASIS OF T-CELL DYSFUNCTION IN CANCER IS INFLUENCED BY THE PARACRINE SECRETION OF TUMOR-DERIVED IL-2

Previously we reported that T cells from mice bearing parental tumors have a variety of functional and biochemical defects when compared wit h T cells from mice bearing IL-2-secreting tumors, The biochemical def ects included reduced levels of several cytoplasmic proteins such as p 56(lck), p59(fyn), and zeta, all of which are known to be critical for signal transduction through the TCR, Based upon these results, we det ermined the consequences of these alterations on downstream signaling events, First, we showed that T cells of parental tumor-bearing mice h ave a reduction of total in vitro kinase activity associated with the TCR/CD3 compared with T cells from mice with IL-2-secreting tumors, Se cond, we observed that following activation, only T cells from IL-2-se creting tumor-bearing mice had completely phosphorylated CD3-associate d zeta-chains and recruited ZAP-70 to cell surface-associated TCR, In contrast, T cells from mice with parental tumors contained incompletel y phosphorylated CD3-associated zeta-chains with little or no TCR-asso ciated ZAP-70, Third, the recruitment of ZAP-70 to the TCR/CD3 complex was seen only in animals with an increase in in vitro p56(lck) kinase activity after T cell activation, Finally, we report that these defec ts in T cell signaling were associated with generalized anergy in vivo , Our findings provide a molecular basis to explain T cell suppression of mice with parental tumors and offer a hypothesis to explain the pr otective effect of tumor-derived IL-2.