Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma
Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma
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DOI：
10.1126/scitranslmed.aal4712
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发表时间：
2017-09-13
影响因子：
17.1
通讯作者：
Swartz, Melody A.
中科院分区：
文献类型：
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作者：
Fankhauser, Manuel;Broggi, Maria A. S.;Swartz, Melody A.
在黑色素瘤中，血管内皮生长因子C(VEGF-C)的表达和随后的淋巴管生成与转移和预后不良有关。血管内皮生长因子-C还促进肿瘤免疫抑制，提示淋巴管生成抑制剂可能与免疫治疗联合应用于临床。我们在使用血管内皮生长因子受体-3(VEGFR-3)阻断抗体的小鼠黑色素瘤模型中提出了这一概念，并出人意料地发现，血管内皮生长因子-C信号增强而不是抑制免疫治疗的反应。我们进一步发现，这种作用是由血管内皮生长因子-C诱导的CCL21和免疫治疗前肿瘤的幼稚T细胞的浸润所介导的，因为CCR7的阻断逆转了血管内皮生长因子-C的增强作用。在人类转移性黑色素瘤中，血管内皮生长因子-C的基因表达与CCL21和T细胞炎症密切相关，血清血管内皮生长因子-C浓度与多肽疫苗接种后T细胞的激活和扩增以及对检查点阻断的临床反应有关。我们认为，VEGF-C通过吸引免疫治疗诱导的肿瘤细胞杀伤而局部激活的初始T细胞来加强免疫治疗，并且血清VEGF-C可以作为免疫治疗反应的预测生物标志物。
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 naive 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 naive 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.