Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses.
The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cells (DCs) and the induction of primary immune responses in vivo. Sorafenib, but not sunitinib, inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, major histocompatibility complex, and costimulatory molecules in response to TLR ligands as well as by their impaired ability to migrate and stimulate T-cell responses. These inhibitory effects are mediated by inhibition of PI3 and MAP kinases and NFkappaB signaling. In contrast, sorafenib had no influence on the phenotype and proliferation of T cells. To analyze the effects of both TKIs on cytotoxic T-cell induction in vivo, C57BL/6 mice were pretreated with sorafenib or sunitinib and immunized with OVA(257-264) peptide. Sorafenib, but not sunitinib, application significantly reduced the induction of antigen-specific T cells. Numbers of regulatory T cells were reduced in peripheral blood mononuclear cells from mice treated with sunitinib. These results indicate that sunitinib, but not sorafenib, is suitable for combination with immunotherapeutic approaches for treatment of cancer patients.
Hipp
Madeleine M
MM
Department of Hematology, Oncology and Immunology, University of Tübingen, Tübingen, Germany.
Hilf
Norbert
N
Walter
Steffen
S
Werth
Daniela
D
Brauer
Katharina M
KM
Radsak
Markus P
MP
Weinschenk
Toni
T
Singh-Jasuja
Harpreet
H
Brossart
Peter
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001557:Benzenesulfonates / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D003911:Dextrans / Q000493:pharmacokinetics; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D000077157:Sorafenib; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D016207:Cytokines; D003911:Dextrans; D007211:Indoles; D010671:Phenylurea Compounds; D011725:Pyridines; D011758:Pyrroles; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D015847:Interleukin-4; D009536:Niacinamide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000077157:Sorafenib; D000077210:Sunitinib