In vivotreatment with interferon causes augmentation of IL-2 induced lymphokine-activated killer cells in the organs of mice

Abstract

SUMMARYInterferon-alpha (IFN-a) has been shown to synergize with IL-2 in the regression ofa variety of established murine tumours and studies are underway to explore this combination in patients with advanced cancers as well. To understand the mechanism of synergy we have studied lymphokineactivated killer (LAK) cell activity in various compartments of mice in response to IFN-a and IL-2 administration. The effects of IFN-y, TNF-a and IL-4 were also examined. C57BL/6 mice were injected intraperitoneally with HBSS, IL-2 alone, IFN-a alone or both, two times a day for 7 days. On days 4 and 8, LAK activity was tested in a 4-h chromium release in cells obtained from lungs, spleen, and liver using fresh MCA-102 tumour cells as targets. The cells from control mice failed to lyse the MCA-102 target. IL-2 caused the generation of LAK activity and an increase in total cell yield in all the organs after 3 days of injection. IFN-a failed to generate LAK activity but when administered along with IL-2, caused synergistic enhancement of LAK lysis of MCA-102 target cells. Cell yield in this group was lower as compared with the IL-2-treated group. LAK activity tested after 7 days of IL-2 therapy was significantly decreased compared with that observed after 3 days. However, activity remained at as high a level after 7 days of therapy as after 3 days of therapy in animals treated with IFN-a and IL-2. FACS analysis revealed that asialo GM-1+ (ASGM-1) and NKI.1+ cells were increased in number in IL-2 and IL-2 plus IFN-a-treated spleen; however, the number ofthese cells was similar in both groups. In the liver, ASGM-1 + cells were higher in the IL-2 plus IFN-a group than in the group treated with IL-2 alone. By in vitro depletion utilizing antibody and Rbc' experiments, it was clear that both ASGM-1 + and NK 1.1 + cells from the spleen mediated most ofthe cytotoxicity of MCA-102 targets. Pre-treatment irradiation (5 Gy) of mice completely abrogated the capability of IL-2 or IL-2 plus IFN-a to generate LAK activity. IFN-y also had a stimulatory effect on lL-2 induction of LAK activity. Tumour necrosis factor-alpha (TNF-a) and IL-4 failed to generate LAK activity and, in combination with IL-2, no additional stimulatory effect was observed. These studies indicate that induction of LAK activity may be at least partly responsible in the mediation of synergistic anti-tumour effects of IFN-a and IL-2 or IFN-y and IL-2.