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.

Genome-wide association study identifies 17 new loci influencing concentrations of circulating cytokines and growth factors

“…A genetic variant in VEGFA was here associated with increased circulating VEGF and shown to have a causal cascade effect on IL7, IL10, IL13 and IL12p70 (Fig 2C-D). Axitinib, a VEGF-receptor inhibitor, has been shown to reduce IL12p70 production in cultured monocyte-derived dendritic cells 29 , which support our findings. Furthermore, VEGFA-transcription follows the same temporal pattern with IL7 transcription during wound healing, and it has been suggested that the secretion of these two cytokines might be connected by the same pathway 30 .…”

The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway

“…2D). We used the tyrosine kinase inhibitor axitinib, which blocks VEGF receptor signaling (35), and bevacizumab, an anti-VEGF neutralizing antibody (36), to mechanistically link circulating VEGF and Jagged1 induction. Both axitinib and bevacizumab inhibited Jagged1 induction in ECs (Fig.…”

Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment

“…Conversely, inhibition of VEGF-signaling during DC maturation in vitro or by treating tumor-bearing mice with sunitinib in vivo has previously been demonstrated to inhibit DC activation [20, 21]. Therefore, we investigated if combining anti-CD40 mAb therapy with sunitinib treatment affects the activation status of conventional DCs (cDCs) (B220 − CD11b +/− CD11c + ) in the tumor draining lymph node.…”

“…While the main antitumor effects of agonistic anti-CD40 antibodies are through activation of DCs, sunitinib has been shown to decrease DC activation [20, 21]. However, CD40-induced DC activation was not hampered by co-treatment with sunitinib in neither the B16.F10 melanoma model nor the T241 fibrosarcoma model (Figure 2A-2B).…”