T regulatory cells (Treg) in patients with metastatic renal cell carcinoma (mRCC) decrease during sunitinib treatment: Correlations with clinical responses and T helper 1/T helper 2 (Th1/Th2) bias

Abstract

2526 Background: High numbers of regulatory T cells (Treg) and high expression of forkhead box transcription factor (FoxP3) in Treg are associated with decreased survival in various malignancies, likely via immunosuppression. Studies demonstrate Th1 suppression (IFN-γ) and Th2 (Il-4) promotion in metastatic renal cell carcinoma (mRCC) patients (pts). The aim of the present study was to determine the profile of Th1, Th2, and Treg at baseline and after 28 days of therapy with the multi-targeted tyrosine kinase inhibitor, sunitinib malate (SU11248). Further, correlation of changes in these parameters and tumor shrinkage (TS) was examined. Methods: Blood was obtained from cytokine-refractory, clear cell mRCC pts on day 1 (pre-treatment) and after 28 days of sunitinib 50mg daily. T cell cytokine expression (IL-4, IFN-γ), percentage in peripheral blood mononuclear cells of CD3+/CD4+/CD25hi+/FoxP3+ cells, and percentage of Treg that were FoxP3+ were evaluated using flow cytometry. Tumor measurements were performed after 2 cycles of therapy. Correlations between immune parameters and TS were assessed with Spearman rank correlations. Results: Ten pts were evaluable for Th1/Th2 responses; 9 for Treg. At baseline 7/10 had Th2 bias and 3/10 had Th1 bias. On day 28, pts maintained Th1 bias (n=3), switched to Th1 bias (n=3), or had decrease in magnitude of Th2 response (n=4). Additionally, a median 74.5% decrease occurred after 28 days of sunitinib in the percentage of CD3/CD4/CD25hi+/FoxP3+ in peripheral blood mononuclear cells, with a median 68.0% decrease of FoxP3+ Treg (CD3/CD4/CD25hi+) cells. Decrease in number of Treg correlated with relative change in Th1 response and Th2 bias (p<.05 for all correlations). All pts had TS including 2 pts with partial response. Degree of TS correlated with relative change in Th1 response (p=.03), and Th2 bias (p=.06), as well as the relative change in FoxP3+ Treg (p=.06). Conclusions: Our results suggest that sunitinib promotes an immunostimulatory Th1 bias and reduces Treg. This immunostimulatory mechanism may contribute to the anti-tumor effect in mRCC. Further studies are on-going. [Table: see text]