title: Immunomodulatory effects of sorafenib on peripheral immune effector cells in metastatic renal cell carcinoma.
abstract: BACKGROUND
  Tyrosine kinase inhibitors (TKI) such as sorafenib have substantially improved the prognosis of metastatic renal cell carcinoma (mRCC) patients, but long-term remissions have only been reached with immunotherapy. Sequencing or combining TKI treatment with immunotherapy may represent an attractive therapeutic concept. However, in vitro data have shown that TKI may not only affect tumour cells, but also inhibit signalling in immune effector cells. Therefore, we asked whether sorafenib had an influence on peripheral immune effector cells in a cohort of 35 mRCC patients receiving sorafenib treatment.
  
  
  METHODS
  Peripheral blood (pB) samples were analysed at baseline and after 8 weeks of treatment. IL-10 and TGF-ß mRNA levels were quantified by RT-PCR; regulatory T cell (Treg) counts and intracellular cytokine responses (TNF-α, IFN-γ, IL-10 and TGF-ß) of mononuclear cell subsets were determined by flow cytometry after in vitro stimulation with PMA/ionomycin.
  
  
  RESULTS
  Sorafenib did not alter the elevated TGF-ß and IL-10 mRNA levels or elevated frequencies of IL-10 and TGF-ß producing monocytes and had no influence on type 1 cytokine responses in pB. CD4+CD25(high) FOXP3+/CD3+ T cells, likely representing Treg cells, decreased during sorafenib therapy.
  
  
  CONCLUSIONS
  In vivo, sorafenib treatment was associated with a decrease in frequency of Treg cells without influencing the function of peripheral immune effector cells. Therefore, although sorafenib did not convert the immunosuppressive phenotype associated with mRCC, it seemed to be a possible candidate for combination with immunotherapy.
authors.affiliation: Department of Medicine III (Hematology and Oncology), Charité, Campus Benjamin Franklin, Berlin, Germany. antonia.busse@charite.de
authors.forename: Antonia
authors.initials: A
authors.lastname: Busse
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Asemissen
authors.forename: Anika
authors.initials: A
authors.lastname: Nonnenmacher
authors.forename: Floriane
authors.initials: F
authors.lastname: Braun
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ochsenreither
authors.forename: David
authors.initials: D
authors.lastname: Stather
authors.forename: Alberto
authors.initials: A
authors.lastname: Fusi
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmittel
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thiel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keilholz
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000276:immunology* / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000276:immunology* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology* / Q000627:therapeutic use; D016753:Interleukin-10 / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000276:immunology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D000077157:Sorafenib; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D016207:Cytokines; D007155:Immunologic Factors; D010671:Phenylurea Compounds; D011725:Pyridines; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D009536:Niacinamide; D000077157:Sorafenib