title: Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients.
abstract: Tyrosine kinase inhibitors (TKIs) as sorafenib are known to reduce the number of immunosuppressive regulatory T cells (Tregs) in the peripheral blood and thereby shifting the immune balance to a more stimulating setting. The effect of sorafenib on intratumoural Tregs is unclear but important for future combinations of TKIs and immunotherapy. We, therefore, evaluated the accumulation of regulatory T cells (Tregs, defined as, CD4(+)FoxP3(+)CD25(high)CD127(low)-cells) in blood, ascites, metastases and primary tumours of patients with renal cell carcinoma (RCC), and we explored the effect of neoadjuvant treatment with sorafenib 400 mg bid on intratumoural Tregs in 11 patients with RCC in comparison to 15 nontreated RCC patients. We found that immunosuppressive Tregs specifically accumulate in primary tumour, metastases and ascites of RCC-patients. Tumour infiltrating Tregs were functional. Neoadjuvant sorafenib treatment significantly reduced the percentage of tumour-infiltrating Tregs (mean 17.3% vs. 28.1%, p = 0.046). Diminished Treg accumulation at the tumour site adds to explain the clinical effectiveness of sorafenib treatment. This observation may have important implications for the use of sorafenib in combination with immunotherapy in patients with RCC, since the depletion of Tregs has been associated with enhanced responses on vaccine mediated immunotherapy.
authors.affiliation: Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ingrid M E
authors.initials: IM
authors.lastname: Desar
authors.forename: J Hans F M
authors.initials: JH
authors.lastname: Jacobs
authors.forename: Christina A
authors.initials: CA
authors.lastname: Hulsbergen-vandeKaa
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Peter F A
authors.initials: PF
authors.lastname: Mulders
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.forename: Carla M L
authors.initials: CM
authors.lastname: van Herpen
authors.forename: I Jolanda J M
authors.initials: IJ
authors.lastname: de Vries
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects*; D020360:Neoadjuvant Therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib