Interferon-γ Is Induced in Human Peripheral Blood Immune Cells In Vitro by Sodium Stibogluconate/Interleukin-2 and Mediates Its Antitumor Activity In Vivo

Abstract

Sodium stibogluconate (SSG), an inhibitor of SHP-1 that negatively regulates cytokine signaling and immunity, suppressed growth of murine Renca tumors in combination with interleukin-2 (IL-2) via a T-cell-dependent mechanism. The ability of SSG to interact with IL-2 in activating primary human immune cells was evaluated herein by assessing its induction of interferon (IFN)-γ⁺ TH1 cells in human peripheral blood in vitro. The significance of IFN-γ⁺ cells was also investigated by assessing SSG/IL-2 antitumor activity in wild-type and IFN-γ^−/− mice. IFN-γ⁺ cells but not IL-5⁺ cells were induced markedly (9.1×) in healthy peripheral blood by SSG/IL-2 in contrast to the modest induction by SSG alone (2.1×) at its clinically achievable dose (20 μg/mL) or by IL-2 (3.1×) at its C _max of low-dose schedule (30 IU/mL). SSG at a higher dose (100 μg/mL) was less effective alone (1.5×) or in combination with IL-2 (7.8×). Peripheral IFN-γ⁺ cells were induced after 4 or 16 h treatment with SSG/IL-2 within CD4⁺ and CD8⁺ lymphocytes coincided with heightened CD69 expression (∼3–4×). SSG/IL-2 was also more effective than the single agents in inducing IFN-γ⁺ cells in the peripheral blood of melanoma patients, whose basal IFN-γ⁺ cell levels were ∼5% of healthy controls. Renca tumor growth was inhibited by SSG/IL-2 in wild-type but not IFN-γ^−/− mice. These results demonstrate SSG interactions with IL-2 in vitro to activate key antitumor immune cells in peripheral blood of healthy and melanoma donors, providing further evidence for proof of concept clinical trials for effecting augmentation of IL-2 through inhibiting negative regulatory protein tyrosine phosphatases.