title: The VEGF-Receptor Inhibitor Axitinib Impairs Dendritic Cell Phenotype and Function.
abstract: Inhibitors of VEGF receptor (VEGFR) signaling such as sorafenib and sunitinib that are currently used in the treatment of malignant diseases have been shown to affect immunological responses by inhibition of the function of antigen presenting cells and T lymphocytes. The VEGFR-inhibitor axitinib has recently been approved for second line therapy of metastatic renal cell carcinoma. While there is some evidence that axitinib might interfere with the activation of T cells, not much is known about the effects of axitinib on dendritic cell (DC) phenotype and function. We here show that the addition of axitinib during the final Toll-like receptor-4-induced maturation step of monocyte-derived human DCs results in a reduced DC activation characterized by impaired expression of activation markers and co-stimulatory molecules such as CD80, CD83 and CD86. We further found a decreased secretion of interleukin-12 which was accompanied by reduced nuclear expression of the transcription factor cRel. In addition, we found a dose-dependent reduced activation of p38 and STAT3 in axitinib-exposed DCs, whereas the expression was not affected. The dysfunction of axitinib-exposed DCs was further underlined by their impaired induction of allogeneic T cell proliferation in a mixed lymphocyte reaction assay and inhibition of DC migration. Our results demonstrate that axitinib significantly affects DC differentiation and function primarily via the inhibition of the nuclear factor kappa B signaling pathway leading to impaired T cell activation. This will be of importance for the design of future vaccination protocols and therapeutic approaches aiming at combining different treatment strategies, eg such as programmed death-1 inhibitors with axitinib.
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.
authors.forename: Annkristin
authors.initials: A
authors.lastname: Heine
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.
authors.forename: Stefanie Andrea Erika
authors.initials: SA
authors.lastname: Held
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.
authors.forename: Solveig Nora
authors.initials: SN
authors.lastname: Daecke
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.
authors.forename: Kati
authors.initials: K
authors.lastname: Riethausen
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kotthoff
authors.affiliation: Institute of Experimental Immunology (IEI), University Bonn, Bonn, Germany.
authors.forename: Chrystel
authors.initials: C
authors.lastname: Flores
authors.affiliation: Institute of Experimental Immunology (IEI), University Bonn, Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.affiliation: Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077784:Axitinib; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D007093:Imidazoles; D007191:Indazoles; D020569:Proto-Oncogene Proteins c-rel; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D000077784:Axitinib; D048051:p38 Mitogen-Activated Protein Kinases