AK-5 tumor-induced modulation of host immune function: upregulation of Th-1-type cytokine response mediates early tumor regression.

Abstract

AK-5, a rat histiocytoma, grows as ascites and undergoes spontaneous regression upon subcutaneous transplantation. Earlier studies from this laboratory have demonstrated that immunogenic rejection of AK-5 tumor is mediated through ADCC involving CD8+ NK cells and anti-AK-5 antibody. Upon subcutaneous transplantation, 55-60% of animals initiated tumor regression between 12-15 days after tumor transplantation (early rejectors), while 40-45% did not evoke regression up to 20-25 days (late rejectors). In order to delineate this differential response among syngeneic animals to the same tumor, we have evaluated the cytokine profiles in circulation of both early and late rejecting animals. Our results show that an increase in IL-2, IFN-gamma, IL-4, IL-12 and TNF-alpha contributed to early regression, suggesting a predominantly Th-1 type of cytokine function being evoked against AK-5 tumor. Hosts with lower circulating levels of these cytokines showed delayed tumor regression. In addition, administration of anti-IL-4/anti-IL-4 + anti-IL-10 lead to a decreased antibody response to AK-5 surface antigens in vivo. Neutralization of IFN-gamma in tumor-bearing animals resulted in inhibition of NK-cell-mediated cytotoxicity against AK-5 cells and delayed the regression process. The present study suggests that early regression of AK-5 tumor depends primarily on the higher levels of circulating Th-1-type cytokines; however, the role of IL-4 and anti-AK-5 antibody in tumor regression cannot be ruled out.