Format

Send to

Choose Destination
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.

Author information

1
Institute of Bioengineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
2
Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.
3
Department of Oncology and Ludwig Cancer Research, University of Lausanne, Lausanne, Switzerland.
4
Department of Cell, Developmental and Cancer Biology and Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
5
The Bioinformatics and Biostatistics Core Facility, EPFL, Lausanne, Switzerland.
6
Swiss Institute for Experimental Cancer Research, School of Life Sciences, EPFL, Lausanne, Switzerland.
7
Institute of Bioengineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland. melodyswartz@uchicago.edu.
8
The Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.

Abstract

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.

PMID:
28904226
DOI:
10.1126/scitranslmed.aal4712
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center