Sodium Stibogluconate Interacts with IL-2 in Anti-Renca Tumor Action via a T Cell-Dependent Mechanism in Connection with Induction of Tumor-Infiltrating Macrophages

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 (Mφ). A combination of SSG and IL-2 was more effective in inhibiting tumor growth (91%) and inducing tumor-infiltrating Mφ (4-fold), whereas IL-2 alone had little effect. Mφ 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 Mφ 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-γ 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-γ capable of activating tumoricidal Mφ. 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-γ production and expansion/activation of Mφ. Our findings suggest that SSG might improve anti-RCC efficacy of IL-2 therapy by enhancing antitumor immunity.

The Protein Tyrosine Phosphatase SHP-1 Modulates the Suppressive Activity of Regulatory T Cells

“…First, SSG due to its ability to inhibit SHP-1 has been shown to enhance Tcon effector function (24, 38). When we tested the effect of SSG under suboptimal peptide concentrations where SSG augments Tcon cell proliferation (Fig.…”

Phase I Dose Escalation Study of Sodium Stibogluconate (SSG), a Protein Tyrosine Phosphatase Inhibitor, Combined with Interferon Alpha for Patients with Solid Tumors

“…No clinical responses were observed, despite the known biological activity of SSG in a number of animal experimental systems 17 where SSG alone or in combination with IFN-α 2b, demonstrated antitumor activity against prostate cancer xenografts 18. In another experiment of SSG plus IL-2, antitumor activity against renal cell carcinoma in mice was enhanced and mediated through an immune mechanism involving IFN-γ 19.…”

Tyrosine Phosphatase Inhibitor-3 Sensitizes Melanoma and Colon Cancer to Biotherapeutics and Chemotherapeutics

“…Following staining, the samples were washed 3 times, re-suspended in 200 μl of 1% para-formaldehyde solution and analyzed (20,000 cells/sample) using a BD FACS Caliburs cytometer as described previously (32, 33). …”

“…The array was consisted of formalin-fixed, paraffin-embedded tissues of human melanoma samples of radial growth phase (15) or vertical growth phase (11) and tissue samples of non-malignant human nevus (5). Sections of the array were prepared and stained for IHC (32) with a commercial MKP1 antibody (sc-1109, Santa Cruz Biotech, Santa Cruz, CA) that was reported for IHC detection of the human molecule (37). The relative MKP1 staining levels in melanoma cells and adjacent benign melanocytes in the tissue samples were estimated via microscopy.…”