Interferon-gamma is induced in human peripheral blood immune cells in vitro by sodium stibogluconate/interleukin-2 and mediates its antitumor activity in vivo.
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)-gamma(+) TH1 cells in human peripheral blood in vitro. The significance of IFN-gamma(+) cells was also investigated by assessing SSG/IL-2 antitumor activity in wild-type and IFN-gamma(-/-) mice. IFN-gamma(+) cells but not IL-5(+) cells were induced markedly (9.1x) in healthy peripheral blood by SSG/IL-2 in contrast to the modest induction by SSG alone (2.1x) at its clinically achievable dose (20 microg/mL) or by IL-2 (3.1x) at its C(max) of low-dose schedule (30 IU/mL). SSG at a higher dose (100 microg/mL) was less effective alone (1.5x) or in combination with IL-2 (7.8x). Peripheral IFN-gamma(+) cells were induced after 4 or 16 h treatment with SSG/IL-2 within CD4(+) and CD8(+) lymphocytes coincided with heightened CD69 expression (approximately 3-4x). SSG/IL-2 was also more effective than the single agents in inducing IFN-gamma(+) cells in the peripheral blood of melanoma patients, whose basal IFN-gamma(+) cell levels were approximately 5% of healthy controls. Renca tumor growth was inhibited by SSG/IL-2 in wild-type but not IFN-gamma(-/-) 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.
Fan
Keke
K
Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Borden
Ernest
E
Yi
Taolin
T
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D000967:Antimony Sodium Gluconate / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D015848:Interleukin-5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D037181:Lectins, C-Type; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000967:Antimony Sodium Gluconate; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D007371:Interferon-gamma; D007376:Interleukin-2; D015848:Interleukin-5; D037181:Lectins, C-Type; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D000099192:CD69 Antigens