Studies suggest that IL-10 may contribute to tumor-associated immunosuppression. In the current study we evaluated the capacity of human non-small cell lung cancer (NSCLC) cell lines to induce PBL IL-10 production. We observed a 10- to 100-fold increase in human PBL IL-10 production following exposure to NSCLC cell supernatants. The tumor-induced increase in PBL IL-10 production was partially blocked by pretreatment of the tumors with the PG inhibitor indomethacin. NSCLC lines were found to constitutively produce PGE2. Exogenous PGE2 also induced PBL IL-10 production in a dose- and time-dependent manner. Both PGE2 and NSCLC supernatant-induced PBL IL-10 production were due to an increase in the IL-10 mRNA transcriptional rate. To evaluate the significance of tumor-induced lymphocyte IL-10 production, the capacity of PBL to produce IFN-gamma during culture in tumor supernatants was assessed in the presence of specific anti-IL-10 mAb. We found enhanced PBL IFN-gamma production following anti-IL-10 treatment. These in vitro studies imply that NSCLC-induced PBL IL-10 production may serve to shift the Th1/Th2 cytokine axis at the tumor site and thus inhibit cell-mediated anti-tumor immune responses. These findings identify a mechanism by which lung cancer cells may escape host immune surveillance. We conclude that NSCLC-derived soluble mediators, including PGs, may play an immunoregulatory role through induction of lymphocyte IL-10 production.