REVERSAL OF MULTIPLE-SITE TUMOR CELL-INDUCED IMMUNOSUPPRESSION BY SPECIFIC CYTOKINES AND PHARMACOLOGICAL AGENTS

The present study explores a model for tumor cell-induced immunosuppre ssion and reversal of suppression by cytokines and other pharmacologic al agents. To simulate tumor-cell-induced suppression, a panel of supp ressor agents which included CsA (cyclosporin A), SSP (staurosporine), BSO (L-buthionine-[S,R]-sulfoximine) and PMA, and a panel of anti-sup pressor agents which included IL-2, IL-4, GSH (glutathione) and amilor ide, were tested. These suppressor/anti-suppressor agents acted differ ently on four specific sites of the immune arm that affected the alpha CD3-induced T cell proliferative and cytotoxic responses. They includ ed (1) IL-2 production, (2) PKC-regulated cytolytic granule production , (3) GSH-regulated maturation of functional granules, and (4) granule exocytosis. When a single suppressor agent was used, all the suppress or agents tested in this study inhibited the generation of alpha CD3-i nduced activated killer cells (CD3-AK), whereas alpha CD3-induced prol iferation was inhibited by CsA, BSO, and EL-4 tumor cells. Except for EL-4, suppression induced by a single suppressor agent could be correc ted by an appropriate single anti-suppressor agent. Multiple suppresso r agents induced profound suppression of CD3-AK response. In most case s, multiple anti-suppressor agents were required to correct the immune defects induced by multiple suppressor agents. Finally, EL-4 tumor-ce ll-induced immunosuppression could not be corrected by any single anti -suppressor agent tested, but a combination of IL-4, GSH and amiloride fully restored the CDS-AK response. These results suggest that tumor cells may induce multiple immune defects that require multiple anti-su ppressor agents for correcting the defects to restore the host immunoc ompetence.