Reversal of multiple-site tumor cell-induced immunosuppression by specific cytokines and pharmacological agents.
The present study explores a model for tumor cell-induced immunosuppression and reversal of suppression by cytokines and other pharmacological agents. To simulate tumor-cell-induced suppression, a panel of suppressor agents which included CsA (cyclosporin A), SSP (staurosporine), BSO (L-buthionine-[S,R]-sulfoximine) and PMA, and a panel of anti-suppressor agents which included IL-2, IL-4, GSH (glutathione) and amiloride, were tested. These suppressor/anti-suppressor agents acted differently on four specific sites of the immune arm that affected the alpha CD3-induced T cell proliferative and cytotoxic responses. They included (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 suppressor agents tested in this study inhibited the generation of alpha CD3-induced activated killer cells (CD3-AK), whereas alpha CD3-induced proliferation was inhibited by CsA, BSO, and EL-4 tumor cells. Except for EL-4, suppression induced by a single suppressor agent could be corrected by an appropriate single anti-suppressor agent. Multiple suppressor agents induced profound suppression of CD3-AK response. In most cases, multiple anti-suppressor agents were required to correct the immune defects induced by multiple suppressor agents. Finally, EL-4 tumor-cell-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 CD3-AK response. These results suggest that tumor cells may induce multiple immune defects that require multiple anti-suppressor agents for correcting the defects to restore the host immunocompetence.
Division of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Ting
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Wang
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Hargrove
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D016207:Cytokines / Q000494:pharmacology*; D005089:Exocytosis / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D053804:Granzymes; D007108:Immune Tolerance / Q000187:drug effects*; D007121:Immunocompetence / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D008222:Lymphokines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology*; D012697:Serine Endopeptidases / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007166:Immunosuppressive Agents; D008222:Lymphokines; D015847:Interleukin-4; D000584:Amiloride; D053804:Granzymes; D012697:Serine Endopeptidases; D005978:Glutathione