Fankhauser, ManuelBroggi, Maria A. S.Potin, LambertBordry, NatachaJeanbart, LauraLund, Amanda W.Da Costa, ElodieHauert, SylvieRincon-Restrepo, MarcelaTremblay, ChristopherCabello, ElenaHomicsko, KrisztianMichielin, OlivierHanahan, DouglasSpeiser, Daniel E.Swartz, Melody A.2017-10-092017-10-092017-10-09201710.1126/scitranslmed.aal4712https://infoscience.epfl.ch/handle/20.500.14299/141191WOS:000410560500003In melanoma, vascular endothelial growth factor-C (VEGF-C) expression and consequent lymphangiogenesis correlate with metastasis and poor prognosis. VEGF-C also promotes tumor immunosuppression, suggesting that lymphangiogenesis inhibitors may be clinically useful in combination with immunotherapy. We addressed this concept in mouse melanoma models with VEGF receptor-3 (VEGFR-3)-blocking antibodies and unexpectedly found that VEGF-C signaling enhanced rather than suppressed the response to immunotherapy. We further found that this effect was mediated by VEGF-C-induced CCL21 and tumor infiltration of naive T cells before immunotherapy because CCR7 blockade reversed the potentiating effects of VEGF-C. In human metastatic melanoma, gene expression of VEGF-C strongly correlated with CCL21 and T cell inflammation, and serum VEGF-C concentrations associated with both T cell activation and expansion after peptide vaccination and clinical response to checkpoint blockade. We propose that VEGF-C potentiates immunotherapy by attracting naive T cells, which are locally activated upon immunotherapy-induced tumor cell killing, and that serum VEGF-C may serve as a predictive biomarker for immunotherapy response.text::journal::journal article::research article