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.

在黑色素瘤中，血管内皮生长因子-C（VEGF-C）的表达和随之而来的淋巴管生成与转移和预后不良相关。VEGF-C还可以促进肿瘤的免疫抑制，提示淋巴管生成抑制剂与免疫疗法联合使用可能在临床上有用。我们在具有VEGF受体3（VEGFR-3）阻断抗体的小鼠黑色素瘤模型中解决了这一概念，并意外地发现VEGF-C信号传导增强而不是抑制了对免疫疗法的反应。我们进一步发现，这种作用是在免疫治疗之前由VEGF-C诱导的CCL21和未成熟T细胞的肿瘤浸润介导的，因为CCR7阻断作用逆转了VEGF-C的增强作用。在人类转移性黑色素瘤中，VEGF-C的基因表达与CCL21和T细胞炎症密切相关，和血清VEGF-C浓度与肽疫苗接种后T细胞活化和扩增以及对检查点封锁的临床反应有关。我们提出，VEGF-C通过吸引幼稚的T细胞来增强免疫治疗，这些T细胞在免疫治疗诱导的肿瘤细胞杀伤后被局部激活，并且血清VEGF-C可以作为免疫治疗反应的预测性生物标志物。