MAPK-independent impairment of T-cell responses by the multikinase inhibitor sorafenib.
Sorafenib, originally developed as CRAF inhibitor but soon recognized as a multikinase inhibitor, is currently widely tested for the treatment of different cancers either alone or in combination therapy. However, the clinical success, particularly in immunogenic tumors such as melanoma, was less than anticipated. Because T-cell activation is tightly regulated by a multitude of kinases, we scrutinized effects of sorafenib on immune responses. To this end, comprehensive in vitro studies revealed that the presence of sorafenib concentrations comparable with observed plasma levels in patients strongly impairs the activation of T cells. Notably, even established tumor-specific immune responses are influenced by sorafenib. Indeed, ELISPOT data of peripheral blood lymphocytes obtained from melanoma patients vaccinated against survivin show markedly diminished survivin-specific immune responses in the presence of sorafenib. Surprisingly, inhibition of T-cell activation was not associated with reduced extracellular signal-regulated kinase phosphorylation. In fact, on T-cell receptor stimulation phospho-extracellular signal-regulated kinase and phospho-mitogen-activated protein kinase kinase levels were found to be elevated in the presence of sorafenib, showing the complexity of signal transduction events following T-cell receptor stimulation. In conclusion, our data show that T-cell function is sensitive toward the multikinase inhibitor sorafenib in a mitogen-activated protein kinase-independent fashion. This observation has important implications for the use of sorafenib as therapy for immunogenic cancers.
Houben
Roland
R
Department of Dermatology, University of Wuerzburg, Wuerzburg, Germany.
Voigt
Heike
H
Noelke
Christiane
C
Hofmeister
Valeska
V
Becker
Juergen C
JC
Schrama
David
D
D000906:Antibodies / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism; D001557:Benzenesulfonates / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D000939:Epitopes; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D009570:Nitriles / Q000494:pharmacology; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D010835:Phytohemagglutinins / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000906:Antibodies; D000951:Antigens, Neoplasm; D001557:Benzenesulfonates; D002070:Butadienes; D018106:CD28 Antigens; D017252:CD3 Complex; D000939:Epitopes; D053645:Interleukin-2 Receptor alpha Subunit; D009570:Nitriles; D010671:Phenylurea Compounds; D010835:Phytohemagglutinins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011948:Receptors, Antigen, T-Cell; C113580:U 0126; D009536:Niacinamide; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate