The VEGF-Receptor Inhibitor Axitinib Impairs Dendritic Cell Phenotype and Function

• Published in: PloS one 2015-06, Vol.10 (6), p.e0128897-e0128897
• Main Authors: Heine, Annkristin, Held, Stefanie Andrea Erika, Daecke, Solveig Nora, Riethausen, Kati, Kotthoff, Philipp, Flores, Chrystel, Kurts, Christian, Brossart, Peter
• Format: Article
• Language: English
• Subjects: Angiogenesis; Antigen-presenting cells; Antigens; Apoptosis; Apoptosis - drug effects; Blood & organ donations; Cancer therapies; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; CD80 antigen; CD83 antigen; CD86 antigen; Cell activation; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Clear cell-type renal cell carcinoma; Cytokines; Cytokines - metabolism; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Dendritic Cells - pathology; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Genetic aspects; Hematology; Humans; Imidazoles - pharmacology; Immunology; Indazoles - pharmacology; Inhibition; Inhibitor drugs; Inhibitors; Interleukin; Interleukin 12; Kidney cancer; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kinases; Leukocyte migration; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Medical treatment; Melanoma; Metastases; Mixed leukocyte reaction; Molecular chains; Monocytes; Monocytes - pathology; Oncology; p38 Mitogen-Activated Protein Kinases - metabolism; PD-1 protein; Phenotype; Phenotypes; Phosphorylation - drug effects; Proto-Oncogene Proteins c-rel - metabolism; Renal cell carcinoma; Rheumatology; Signal transduction; Signaling; Stat3 protein; STAT3 Transcription Factor - metabolism; T cell receptors; T cells; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Toll-like receptors; Vaccination; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - metabolism; Vascular endothelial growth factor receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128897

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.