Paradoxical roles of tumor lymphangiogenesis on tumor immunity and implications for immunotherapy - Resubmission 01

项目摘要 在黑色素瘤和其他癌症中，通过VEGF-C在淋巴结中的表达，局部淋巴网络的扩张是通过淋巴结转移来实现的。 肿瘤微环境促进转移并与不良预后广泛相关。我们和其他人 已经表明VEGF-C激活的淋巴管在肿瘤中发挥重要的免疫抑制作用 微环境奇怪的是，我们已经观察到，在小鼠黑色素瘤模型中，淋巴管生成性肿瘤- MORS对免疫治疗更敏感，包括过继性T细胞治疗，树突状细胞疫苗， 蛋白质疫苗在这里，我们提出了一个研究计划，探索肿瘤淋巴管的另一面- 并提出了一种新的假设，即肿瘤微环境中的VEGF-C可以诱导肿瘤的发生， 炎症和免疫抑制，它也增强了幼稚T细胞的浸润，至少部分 通过上调淋巴归巢趋化因子CCL 21这种增强的渗透，反过来，可以启动你- 莫尔用于增强对免疫疗法的反应性。提出了三个目标，以探讨（一）验证和 小鼠模型中的机制基础，（ii）与人黑色素瘤的相关性，以及（iii）翻译应用。 是的。

Project Summary In melanoma and other cancers, the expansion of the local lymphatic network via expression of VEGF-C in the tumor microenvironment promotes metastasis and is widely correlated with poor prognosis. We and others have shown that VEGF-C-activated lymphatic vessels play important immune suppressive roles in the tumor microenvironment. Paradoxically, we have observed that in mouse melanoma models, lymphangiogenic tu- mors were more responsive to immunotherapy, including in adoptive T cell therapy, dendritic cell vaccines, and protein vaccination. Here we propose a research program that explores this other side of tumor lymphangio- genesis, and suggest a novel hypothesis that while VEGF-C in the tumor microenvironment can induce in- flammation and immune suppression, it also enhances the infiltration of naïve T cell infiltration, at least in part by upregulating the lymphoid homing chemokine CCL21. This enhanced infiltration, in turn, can prime the tu- mor for enhanced responsiveness to immunotherapy. Three aims are proposed to explore (i) validation and mechanistic underpinnings in mouse models, (ii) relevance to human melanoma, and (iii) translational applica- tion.