title: Sorafenib, but not sunitinib, induces regulatory T cells in the peripheral blood of patients with metastatic renal cell carcinoma.
abstract: Induction of regulatory T cells (Treg) is an important mechanism leading to tolerance against tumors. Increased levels of Treg have been described in renal cell carcinoma (RCC) patients and seem to correlate with an adverse outcome. Our study aimed to analyze the influence of sorafenib and sunitinib on the frequency of Treg in patients with metastatic RCC (mRCC). Treg were analyzed by flow cytometry in the 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). Blood samples were taken before treatment and during the first, second, and third months of therapy. Flow cytometric analysis of PB mononuclear cells was performed using fluorochrome-labeled antibodies against CD3, CD4, CD25, and FOXp3. During the first month of therapy, patients treated with sorafenib showed a significant increase in FOXp3CD3CD4CD25 Treg (13.5 vs. 36.3% of gated cells, P=0.02, or 0.35 vs. 0.49% of total cells) and the ratio FOXp3 T cells/FOXp3 T cells (0.16 vs. 0.56 of gated cells, P=0.02). These elevated levels persisted throughout the treatment period. There was no influence of sunitinib on the frequency of Treg in our cohort of patients. Sorafenib, but not sunitinib, leads to an early and sustained increase in Treg in PB of mRCC patients. In immunoresponsive tumors such as RCC, immunological effects of kinase inhibitors are particularly relevant for the design of combination trials with immunotherapeutic agents. Our study suggests that sorafenib should be avoided in such a therapeutic setting.
authors.affiliation: Department of Hematology, Charité-University Medicine Berlin, Berlin, Germany. anne.floercken@charite.de
authors.forename: Anne
authors.initials: A
authors.lastname: Flörcken
authors.forename: Anna
authors.initials: A
authors.lastname: Takvorian
authors.forename: Antje
authors.initials: A
authors.lastname: Van Lessen
authors.forename: Anju
authors.initials: A
authors.lastname: Singh
authors.forename: Werner
authors.initials: W
authors.lastname: Hopfenmüller
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Antonio
authors.initials: A
authors.lastname: Pezzutto
authors.forename: Jörg
authors.initials: J
authors.lastname: Westermann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use*; D000077157:Sorafenib; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D017252:CD3 Complex; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D007211:Indoles; D053645:Interleukin-2 Receptor alpha Subunit; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077210:Sunitinib