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Sci Transl Med. 2017 Sep 13;9(407). pii: eaal4712. doi: 10.1126/scitranslmed.aal4712.

Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma.

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Institute of Bioengineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.
Department of Oncology and Ludwig Cancer Research, University of Lausanne, Lausanne, Switzerland.
Department of Cell, Developmental and Cancer Biology and Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
The Bioinformatics and Biostatistics Core Facility, EPFL, Lausanne, Switzerland.
Swiss Institute for Experimental Cancer Research, School of Life Sciences, EPFL, Lausanne, Switzerland.
Institute of Bioengineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
The Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.


In 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 naïve 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 naïve 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.

[Indexed for MEDLINE]

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