Angiopoietin-2/Tie2 signaling regulation of liver metastasis in pancreatic neuroendocrine tumors

血管生成素-2/Tie2信号对胰腺神经内分泌肿瘤肝转移的调控 项目总结 近一半的Pannet患者在确诊时发现有肝转移，而其他许多人则发展为肝脏。 原发肿瘤手术切除后的转移。虽然胰腺神经内分泌的发生率 近几十年来，肿瘤(Pannet)稳步增长，只有有限的治疗选择 转移性全息肉瘤患者。此外，免疫检查点抑制剂(ICI)在 免疫抑制微环境所致的转移性PANET患者。因此，理解 肝转移、免疫逃避的机制及其在ICI治疗耐药中的趋同 在PANNET中迫切需要提高先进的PANNET的临床管理水平。 血管不稳定被认为是肿瘤生长和转移的标志。血管生成素-2 血管紧张素转换酶2(ANG2)与受体酪氨酸激酶Tie2结合，是一种强有力的血管不稳定因子。我们 证明在炎症条件下，Ang2抑制Tie2信号转导，促进血管 失稳和渗漏。重要的是，新出现的证据表明，血管不稳定有助于 通过损害免疫细胞的渗透来逃避肿瘤的免疫。在初步研究中使用了自发的 在Pannet小鼠模型上，我们发现Ang2抑制可以抑制肝转移瘤的生长，并改善 生死存亡。血管紧张素转换酶2的抑制也减少了血管渗漏，增加了转移灶中CD8+T细胞的浸润。 我们以前发现Tie2信号的抑制伴随着Tie2的胞外结构域的切割 辅受体Tie1导致循环中可溶性Tie1(STie1)水平增加。我们的初步研究表明 PANET患者血浆sTie1水平升高对预后有重要意义。 在这个项目中，我们将阐明Ang2介导的肝转移进展的机制。 免疫抑制和抗PD-1治疗抵抗在转移性PANNET中的作用。在目标1中，我们将确定 血管紧张素转换酶2介导的血管失稳在PANet肝转移进展中的作用 人肝转移与自发性和遗传性Ang2缺失及功能阻断抗体的关系 实验性Pannet小鼠模型。从机制上讲，在目标2中，我们将确定Ang2介导的 肝转移瘤中血管渗漏对CD8+T细胞的影响 Ang2抑制联合抗PD-1治疗对转移性胰腺癌的影响。我们将确定Ang2是否 BLOCKED通过促进血管稳定和抗PD-1治疗使泛肝转移瘤对抗PD-1治疗增敏 CD8+T细胞在Pannet小鼠体内的浸润。最后，目标3将在诊断时确定循环中的sTie1水平作为 PANET患者肿瘤侵袭性的潜在生物标记物。本项目圆满完成， 阐明血管调节免疫逃避的潜在机制，可显著增强 转移性PANET的临床处理以及对转移性PANET治疗的启示 源于其他肿瘤类型的疾病，特别是那些对ICI治疗反应不佳的疾病。

Title: Angiopoietin-2/Tie2 signaling regulation of liver metastasis in pancreatic neuroendocrine tumors PROJECT SUMMARY Liver metastases are found in nearly half of PanNET patients at diagnosis while many others develop liver metastasis after surgical resection of the primary tumor. Though the incidence of pancreatic neuroendocrine tumors (PanNET) has increased steadily over recent decades, there are only limited therapeutic options for metastatic PanNET patients. Furthermore, immune checkpoint inhibitors (ICI) showed the limited efficacy in patients with metastatic PanNET due to the immunosuppressive microenvironment. Therefore, understanding the mechanisms underlying liver metastasis, immune evasion, and their convergence on ICI therapy resistance in PanNET is urgently necessary to improve the clinical management of advanced PanNET. Vascular destabilization is recognized as a hallmark of tumor growth and metastasis. Angiopoietin-2 (Ang2), which binds to the receptor tyrosine kinase Tie2, is a potent vascular destabilizing factor. We demonstrated that under inflammatory conditions, Ang2 suppresses Tie2 signaling and promotes vascular destabilization and leakage. Importantly, emerging evidence suggests that vascular destabilization facilitates tumor immune evasion by impairing immune cell infiltration. In preliminary studies using a spontaneous PanNET mouse model, we found that Ang2 inhibition suppresses liver metastatic growth and improves the survival. Ang2 inhibition also reduced vascular leakage and increased CD8+ T-cell infiltration in metastases. We previously showed that suppression of Tie2 signaling is accompanied by ectodomain cleavage of the Tie2 coreceptor, Tie1, resulting in increased circulating levels of soluble Tie1 (sTie1). Our preliminary studies show that elevated plasma sTie1 levels in PanNET patients have significant prognostic implications. In this project, we will elucidate the mechanisms underlying Ang2-mediated liver metastatic progression, immunosuppression, and anti-PD-1 therapy resistance in metastatic PanNET. In Aim 1, we will determine the contribution of Ang2-mediated vascular destabilization to liver metastatic progression in PanNET by using human liver metastases and function-blocking antibodies or genetic Ang2 deletion in spontaneous and experimental PanNET mouse models. Mechanistically, in Aim 2, we will determine whether Ang2-mediated vascular leakage impairs CD8+ T-cell infiltration in liver metastases, serving as the basis for assessing the effects of Ang2 inhibition combined with anti-PD-1 therapy in metastatic PanNET. We will determine if Ang2 blockade sensitizes PanNET liver metastases to anti-PD-1 therapy by promoting vascular stabilization and CD8+ T-cell infiltration in PanNET mice. Finally, Aim 3 will identify circulating levels of sTie1 at diagnosis as a potential biomarker for tumor aggressiveness in PanNET patients. Successful completion of this project, which elucidates the mechanisms underlying vascular regulation of the immune evasion, could significantly enhance the clinical management of metastatic PanNET, as well as provide insights for the treatment of metastatic disease deriving from other tumor types, especially those with poor response to ICI therapy.