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

Inhibitors of VEGF receptor(VEGFR) signaling such as sorafeniband sunitinibthat 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 axitinibhas recently been approved for second line therapyof metastatic renal cell carcinoma. While there is some evidence that axitinibmight interfere with the activation of T cells, not much is known about the effects of axitinibon dendritic cell (DC) phenotype and function. We here show that the addition of axitinibduring 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-12which 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 reactionassay and inhibition of DC migration. Our results demonstrate that axitinibsignificantly 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.