Research ArticleCancer

Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma

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Science Translational Medicine  13 Sep 2017:
Vol. 9, Issue 407, eaal4712
DOI: 10.1126/scitranslmed.aal4712

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Unintentional immunotherapy inhibition

Metastatic spread depends on lymphangiogenesis, and mediators of this pathway are targeted clinically for cancer treatment. Fankhauser et al. used mouse models of melanoma to show that blocking lymphangiogenesis actually disrupted recruitment of naïve T cells and subsequent antitumor immunity. Data from patients enrolled in clinical trials confirmed that indicators of lymphangiogenesis were associated with robust T cell responses. These findings have important implications for the use and predictions of response to immunotherapy.

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.

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