Modulation of regulatory T cells and myeloid-derived suppressor cells by sorafenib and sunitinib in renal cell carcinoma patients

Abstract

e16002 Background: Induction of regulatory T (Treg) and myeloid-derived suppressor cells (MDSC) is a major mechanism for the escape of tumors from immunological control. Increased levels of Treg cells have been described in renal cell cancer (RCC) patients and seem to correlate with an adverse outcome. Furthermore, reduction of Treg has been reported for RCC patients under sunitinib therapy. The aim of our study was to analyse the influence of sorafenib and sunitinib on the frequency of Treg and MDSC in patients with metastatic RCC (mRCC). Methods: The number of T reg, MDSC and lymphocyte subpopulations was analysed by flowcytometry in peripheral blood (pb) of patients (n=19) with histologically confirmed mRCC under treatment with either sunitinib (50 mg/d, n=11) or sorafenib (800 mg/d, n=8). After informed consent blood samples were taken before and during the 1st, 2nd, and 3rd month of therapy. Flowcytometric analysis was performed using fluorochrome labeled antibodies against CD3, CD4, CD8, CD25, CD127, FOXp3, CD33, C14, CD11b and HLA-DR. Results: The baseline level of Treg did not differ from healthy controls. However, there was a significant increase of CD3+CD4+CD25+FOXp3+Treg (13,5% vs. 36,3% of gated cells, p= 0.02) and the ratio FOXp3+/FOXp3- CD3+CD4+ T cells (0,16% vs. 0,56% of gated cells, p= 0.02) in the group of sorafenib-treated patients compared to sunitinib-treated patients during the 1st month of therapy and thereafter. This effect was confirmed in an intragroup analysis. There was no influence of Sunitinib on the frequency of Treg. Analysis of CD33+/HLA-DR-/11b+ MDSC did not reveal any change under treatment with sorafenib or sunitinib. Conclusions: Sorafenib, but not sunitinib, leads to an early and sustained increase of Treg in pb of mRCC patients. A negative influence of sorafenib on primary immune responses has been described and has mainly been attributed to functional impairment of dendritic cells (DC). Whether altered DC function under sorafenib is responsible for the induction of Treg in RCC patients will have to be addressed in future studies. In immunoresponsive tumors such as RCC, immunological effects of kinase inhibitors are particularly relevant for the design of combination trials with immunotherapeutic agents. No significant financial relationships to disclose.