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

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Abstract
Interferon-alpha (IFN-α) has been shown to synergize with IL-2 in the regression or a 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 lymphokine-activated killer (LAK) cell activity in various compartments of mice in response to IFN-α and IL-2 administration. The effects of IFN-γ, TNF-α and IL-4 were also examined. C57BL/6 mice were injected intraperitoneally with HBSS, IL-2 alone, IFN-α 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-α 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-α and IL-2. FACS analysis revealed that asialo GM-1+ (ASGM-1) and NK1.1+ cells were increased in number in IL-2 and IL-2 plus IFN-α-treated spleen; however, the number of these cells was similar in both groups. In the liver, ASGM-1+ cells were higher in the IL-2 plus IFN-α 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 NK1.1+ cells from the spleen mediated most of the cytotoxicity of MCA-102 targets. Pre-treatment irradiation (5 Gy) of mice completely abrogated the capability of IL-2 or IL-2 plus IFN-α to generate LAK activity. IFN-γ also had a stimulatory effect on IL-2 induction of LAK activity. Tumour necrosis factor-alpha (TNF-α) 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-α and IL-2 or IFN-γ and IL-2.

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