title: The kinase inhibitors sunitinib and sorafenib differentially affect NK cell antitumor reactivity in vitro.
abstract: Sunitinib and Sorafenib are protein kinase inhibitors (PKI) approved for treatment of patients with advanced renal cell cancer (RCC). However, long-term remissions of advanced RCC have only been observed after IL-2 treatment, which underlines the importance of antitumor immune responses in RCC patients. Because PKI, besides affecting tumor cells, also may inhibit signaling in immune effector cells, we determined how Sunitinib and Sorafenib influence antitumor immunity. We found that cytotoxicity and cytokine production of resting and IL-2-activated PBMC are inhibited by pharmacological concentrations of Sorafenib but not Sunitinib. Analysis of granule-mobilization within PBMC revealed that this was due to impaired reactivity of NK cells, which substantially contribute to antitumor immunity by directly killing target cells and shaping adaptive immune responses by secreting cytokines like IFN-gamma. Analyses with resting and IL-2-activated NK cells revealed that both PKI concentration dependently inhibit cytotoxicity and IFN-gamma production of NK cells in response to tumor targets. This was due to impaired PI3K and ERK phosphorylation which directly controls NK cell reactivity. However, while Sorafenib inhibited NK cell effector functions and signaling at levels achieved upon recommended dosing, pharmacological concentrations of Sunitinib had no effect, and this was observed upon stimulation of NK cell reactivity by tumor target cells and upon IL-2 treatment. In light of the important role of NK cells in antitumor immunity, and because multiple approaches presently aim to combine PKI treatment with immunotherapeutic strategies, our data demonstrate that choice and dosing of the most suitable PKI in cancer treatment requires careful consideration.
authors.affiliation: Department of Hematology and Oncology, Eberhard Karls-University, Tuebingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Krusch
authors.forename: Julia
authors.initials: J
authors.lastname: Salih
authors.forename: Manuela
authors.initials: M
authors.lastname: Schlicke
authors.forename: Tina
authors.initials: T
authors.lastname: Baessler
authors.forename: Kerstin Maria
authors.initials: KM
authors.lastname: Kampa
authors.forename: Frank
authors.initials: F
authors.lastname: Mayer
authors.forename: Helmut Rainer
authors.initials: HR
authors.lastname: Salih
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D000077157:Sorafenib; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D000077210:Sunitinib