Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma

Manuel Fankhauser, Maria A.S. Broggi, Lambert Potin, Natacha Bordry, Laura Jeanbart, Amanda Lund, Elodie Da Costa, Sylvie Hauert, Marcela Rincon-Restrepo, Christopher Tremblay, Elena Cabello, Krisztian Homicsko, Olivier Michielin, Douglas Hanahan, Daniel E. Speiser, Melody A. Swartz

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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.

Original languageEnglish (US)
Article numbereaal4712
JournalScience Translational Medicine
Volume9
Issue number407
DOIs
StatePublished - Sep 13 2017

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fankhauser, M., Broggi, M. A. S., Potin, L., Bordry, N., Jeanbart, L., Lund, A., Da Costa, E., Hauert, S., Rincon-Restrepo, M., Tremblay, C., Cabello, E., Homicsko, K., Michielin, O., Hanahan, D., Speiser, D. E., & Swartz, M. A. (2017). Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma. Science Translational Medicine, 9(407), [eaal4712]. https://doi.org/10.1126/scitranslmed.aal4712