Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes

Abstract

Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

“…Alfaro et al showed that VEGF pathway inhibition using bevacizumab or sorafenib in vitro abrogated the differentiation of monocytes to DCs [58]. Another in vitro study used embryonic stem cells to show that the DC maturation mainly depends on VEGFR1 activation [59].…”

Effect of siRNA-mediated downregulation of VEGF in Tca8113 cells on the activity of monocyte-derived dendritic cells

“…The functional activity of DCs depends, in part, on the expression of HLA-DR and co-stimulatory molecules (17). effect of VEGF but they expressed less HLA-DR and CD86, and this effect was suspended by the VEGF inhibitor (18).…”

Early experience with targeted therapy and dendritic cell vaccine in metastatic renal cell carcinoma after nephrectomy

“…The use of DC vaccine has also shown promising results in some reported cases in the literature (9). The use of DC vaccine in association with targeted drugs is controversial and was first assumed that it could be used with sunitinib alone, (14) although it could also be used with sorafenib as demonstrated by Alfaro et al (15).…”

“…Apparently, any of these drugs could be used in association with DC vaccine based on the Alfaro et al study (15).…”