Abstract C107: The antitumor activity of SCV‐07 is attributable, in part, to an inhibitory effect on STAT3 driven responses

Introduction: In recent years, agents that boost the immune system to break through tumor‐induced immunosuppression have gained importance. The dipeptide, SCV‐07 (gamma‐D‐glutamyl‐tryptophan) has been shown to be efficacious in reducing progression of renal and lung carcinoma as well as melanoma in mouse models. SCV‐07 also induces the elaboration of Th1 cytokines. Because the dipeptide has an effect on a diverse range of tumors, it is possible that SCV‐07 has a global, antigen‐independent effect on the immune system. Because STAT3 is known to be upregulated in tumor microenvironments, and the effect of STAT3 driven gene expression is global immune suppression of anti‐tumor responses, we conducted the following studies to determine whether SCV‐07 modulates STAT3‐induced responses as part of its mechanism in stimulation of an anti‐tumor immune response. Experimental design: In vitro studies were conducted using B16F0 melanoma cells, transiently transfected with a STAT3 responsive element driving luciferase expression. Cells were incubated with varying concentrations of SCV‐07, and luciferase expression was measured after 24 hours of incubation. In in vivo studies Balb/c mice were injected with B16 melanoma cells and the mice were either left untreated or were treated with SCV‐07 at 5 mg/kg. Tumors were harvested on day 11 and were analyzed by flow cytometry for the presence of P‐STAT3‐positive cells. Results: SCV‐07 inhibited expression of STAT3 driven luciferase expression to the extent of ∼70 – 80%, depending on concentration of SCV‐07. Further studies showed that SCV‐07 additionally inhibited the translocation of STAT3 into the nucleus of HeLa cells. SCV‐07 increased survival and inhibited the progression of melanoma growth in the B16 mouse model, and this inhibition was accompanied by reduced phosphorylated STAT3 staining at the tumor site as well as an influx of natural killer cells. Conclusions: These results provide support that SCV‐07 acts in an antigen independent manner to reduce STAT3 driven gene expression and potentiate anti‐tumor immune responses. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C107.