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，局部淋巴网络通过表达血管内皮生长因子-C在 肿瘤微环境促进肿瘤转移，与预后不良密切相关。我们和其他人 研究表明，血管内皮生长因子-C激活的淋巴管在肿瘤中起着重要的免疫抑制作用 微环境。矛盾的是，我们观察到在小鼠黑色素瘤模型中，淋巴管生成的肿瘤- MORS对免疫治疗更敏感，包括过继T细胞治疗、树突状细胞疫苗和 蛋白质疫苗接种。在这里，我们提出一个研究项目，探索肿瘤淋巴管的另一面-- Genesis，并提出了一个新的假说，即虽然肿瘤微环境中的血管内皮生长因子-C可以诱导- 炎症和免疫抑制，它还增强了幼稚T细胞的渗透，至少在一定程度上 通过上调淋巴归巢趋化因子CCL21。这种增强的渗透，反过来又可以为TU- MOR用于增强对免疫治疗的反应性。提出了三个目标来探索(I)验证和 小鼠模型的机制基础，(Ii)与人类黑色素瘤的相关性，以及(Iii)翻译应用- 提顿。

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.