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.
Autor: Alfaro, C.; Suárez, N.; González, A.; Solano, S.; Erro, L.; Dubrot, J.; Palazón, A.; Hervas-Stubbs, S.; Gurpide, A.; López-Picazo, J.M.; Grande-Pulido, E.; Melero, I.; Pérez-Gracia, J. L.
Resumen: 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.
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