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

• 批准号: 10746299
• 负责人: Minah Kim
• 金额: $ 3.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746299
• 关键词: Angiopoietin-2; Binding; Blocking Antibodies; Blood Vessels; CD8-Positive T-Lymphocytes; Clinical Management; Diagnosis; Disease; Excision; Extravasation; Functional disorder; Genetic; Growth; Human; Immune Evasion; Immune checkpoint inhibitor; Immunosuppression; Impairment; Incidence; Inflammatory; Islet Cell Tumor; Liver; Mediating; Metastatic Neoplasm to the Liver; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Perfusion; Plasma; Primary Neoplasm; Prognosis; Receptor Protein-Tyrosine Kinases; Regulation; Resistance; Role; Signal Transduction; Signaling Molecule; T cell infiltration; TIE-2 Receptor; Therapeutic; Tumor Escape; Tumor Markers; Work; anti-PD1 therapy; cancer biomarkers; checkpoint therapy; immune cell infiltrate; immunoregulation; improved; insight; liver function; mouse model; objective response rate; potential biomarker; prognostic; receptor; response; tumor; tumor growth; tumor progression; tumor-immune system interactions

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.

在诊断中，近一半的Pannet患者发现肝转移，而许多其他患者则发展 原发性肿瘤手术切除后转移。虽然是胰神经内分泌的发生率 肿瘤（Pannet）在最近几十年中稳步增加，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）显示出有限的功效 由于免疫抑制微环境而导致转移性Pannet的患者。因此，理解 肝转移，免疫逃避及其在ICI治疗耐药性上的收敛性的机制 在Pannet中，迫切需要改善晚期Pannet的临床管理。 血管不稳定被认为是肿瘤生长和转移的标志。 Angiopoietin-2 （ANG2）与受体酪氨酸激酶TIE2结合，是一种有效的血管不稳定因子。我们 证明在炎症条件下，Ang2抑制TIE2信号并促进血管 不稳定和泄漏。重要的是，新兴的证据表明血管不稳定促进 通过损害免疫细胞浸润，肿瘤免疫逃避。在初步研究中使用自发的 Pannet小鼠模型，我们发现Ang2抑制抑制了肝转移生长并改善了 生存。 Ang2抑制作用还减少了血管泄漏，CD8+ T细胞浸润增加了转移。 我们先前表明TIE2信号的抑制伴随着TIE2的外域裂解 CORECECTOR，TIE1，导致可溶性TIE1的循环水平升高（STIE1）。我们的初步研究表明 Pannet患者的血浆STIE1水平升高具有显着的预后意义。 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治疗耐药性。在AIM 1中，我们将确定 通过使用Ang2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和 实验pannet小鼠模型。从机械上讲，在AIM 2中，我们将确定Ang2介导的 血管泄漏会损害CD8+ T细胞转移中的CD8+ T细胞浸润，作为评估的基础 Ang2抑制作用在转移性Pannet中结合抗PD-1治疗。我们将确定Ang2是否 封锁通过促进血管稳定和 Pannet小鼠中的CD8+ T细胞浸润。最后，AIM 3将确定诊断时循环水平的STIE1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，该项目 阐明免疫逃避的血管调节的机制，可以显着提高 转移性Pannet的临床管理，并提供了治疗转移性的见解 来自其他肿瘤类型的疾病，尤其是那些对ICI治疗反应不佳的疾病。