Abstract
IL-2 therapy results in 10-20% response rates in advanced renal cell carcinoma (RCC) via activating immune cells, in which the protein tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 (SHP-1) is a key negative regulator. Based on finding that sodium stibogluconate (SSG) inhibited SHP-1, the anti-RCC potential and action mechanism of SSG and SSG/IL-2 in combination were investigated in a murine renal cancer model (Renca). Despite its failure to inhibit Renca cell proliferation in cultures, SSG induced 61% growth inhibition of Renca tumors in BALB/c mice coincident with an increase (2-fold) in tumor-infiltrating macrophages (Mphi). A combination of SSG and IL-2 was more effective in inhibiting tumor growth (91%) and inducing tumor-infiltrating Mphi (4-fold), whereas IL-2 alone had little effect. Mphi increases were also detected in the spleens of mice treated with SSG (3-fold) or SSG/IL-2 in combination (6-fold), suggesting a systemic Mphi expansion similar to those in SHP-deficient mice. T cell involvement in the anti-Renca tumor action of the combination was suggested by the observations that the treatment induced spleen IFN-gamma T cells in BALB/c mice, but failed to inhibit Renca tumor growth in athymic nude mice and that SSG treatment of T cells in vitro increased production of IFN-gamma capable of activating tumoricidal Mphi. The SSG and SSG/IL-2 combination treatments were tolerated in the mice. These results together demonstrate an anti-Renca tumor activity of SSG that was enhanced in combination with IL-2 and functions via a T cell-dependent mechanism with increased IFN-gamma production and expansion/activation of Mphi. Our findings suggest that SSG might improve anti-RCC efficacy of IL-2 therapy by enhancing antitumor immunity.
Highlights
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renal cancer model (Renca) cells cultured in the absence or the presence of sodium stibogluconate (SSG) (6.25–200 g/ml) for 6 days showed similar growth (Fig. 1A), whereas the growth of WM9 melanoma cells was inhibited by SSG in a dose-dependent manner under comparable conditions (Fig. 1B) as reported previously [10]
The results presented in this study demonstrate for the first time a significant anti-Renca tumor activity of SSG that is mediated via an immune mechanism and augmented in the presence of IL-2
Summary
RCC, renal cell carcinoma; M, macrophage; PTP, protein tyrosine phosphatase; SHP-1, Src homology 2 domain-containing phosphatase 1; SSG, sodium stibogluconate. Inhibition of a negative regulatory PTPase of intracellular signaling may play a role in the drug’s anti-Leishmania action This action mechanism provides a rational explanation for the dependency of SSG anti-Leishmania efficacy on host cytokines and immune cells [13,14,15] and for the selective drug sensitivity of the intracellular form, but not the free-living. We report for the first time a potent antiRenca tumor activity of SSG that interacts with IL-2 in a tolerated manner to inhibit Renca tumor growth and functions via a T celldependent mechanism coincident with induction of tumor-infiltrating macrophages (M) and systemic M expansion These results provide the first preclinical proof of concept evidence that SSG could be combined with IL-2 to induce more effective anti-RCC immune action and suggest that refined SHP-1 inhibitors could be developed as safe and efficacious immune activators for therapeutic purposes
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