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

标题：胰腺神经内分泌肿瘤肝转移的血管生成素-2/Tie2信号调节 项目摘要 在诊断时，在近一半的PanNET患者中发现了肝转移，而其他许多患者在诊断时发现了肝转移。 手术切除原发肿瘤后转移。虽然胰腺神经内分泌的发病率 近几十年来，PanNET肿瘤的发病率稳步上升，但只有有限的治疗选择， 转移性PanNET患者。此外，免疫检查点抑制剂（ICI）在治疗中显示出有限的疗效。 由于免疫抑制微环境导致的转移性PanNET患者。因此了解 肝转移、免疫逃避及其对ICI治疗耐药的汇聚机制 在PanNET中的应用是改善先进PanNET临床管理的迫切需要。 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 与受体酪氨酸激酶Tie 2结合的血管生成素2（Ang 2）是一种有效的血管去稳定因子。我们 表明在炎症条件下，Ang 2抑制Tie 2信号传导并促进血管生成。 不稳定和泄漏。重要的是，新出现的证据表明，血管不稳定促进 通过损害免疫细胞浸润的肿瘤免疫逃避。在初步研究中， 在PanNET小鼠模型中，我们发现Ang 2抑制肝转移生长并改善肝转移。 生存Ang 2抑制还减少了转移瘤中的血管渗漏并增加了CD 8 + T细胞浸润。 我们先前表明Tie 2信号传导的抑制伴随着Tie 2的胞外域切割， 辅助受体Tie 1，导致可溶性Tie 1（sTie 1）的循环水平增加。我们的初步研究显示 PanNET患者血浆sTie 1水平升高具有显著的预后意义。 在这个项目中，我们将阐明Ang 2介导的肝转移进展的机制， 免疫抑制和抗PD-1治疗耐药性。在目标1中，我们将确定 通过使用Ang 2介导的血管不稳定对PanNET肝转移进展的贡献 人肝转移和功能阻断抗体或自发性和 实验PanNET小鼠模型。从机制上讲，在目标2中，我们将确定Ang 2介导的 血管渗漏损害了肝转移瘤中的CD 8 + T细胞浸润，作为评估肝转移瘤的基础。 Ang 2抑制联合抗PD-1治疗在转移性PanNET中的作用。我们将确定Ang 2是否 阻断通过促进血管稳定化使PanNET肝转移对抗PD-1治疗敏感， PanNET小鼠中的CD 8 + T细胞浸润。最后，目标3将确定诊断时sTie 1的循环水平， PanNET患者肿瘤侵袭性的潜在生物标志物。成功完成该项目， 阐明了免疫逃避的血管调节机制，可以显着增强 转移性PanNET的临床管理，以及为转移性PanNET的治疗提供见解。 来自其他肿瘤类型的疾病，尤其是对ICI治疗反应差的肿瘤。

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.