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

Keke Fan, Ming Zhou, Manas K. Pathak, Daniel J. Lindner, Cengiz Z. Altuntas, Vincent K. Tuohy, Ernest C. Borden, Taolin Yi

Research output: Contribution to journalArticle

14 Scopus citations

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 fading 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 marine 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.

Original languageEnglish (US)
Pages (from-to)7003-7008
Number of pages6
JournalJournal of Immunology
Volume175
Issue number10
DOIs
StatePublished - Nov 15 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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