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

基本信息

批准号：
10663955
负责人：
Minah Kim
金额：
$ 38.29万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-12 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663955
关键词：
ANGPT2 gene Agonist Angiopoietin-2 Binding Biological Markers Blocking Antibodies Blood Vessels CD8-Positive T-Lymphocytes Cell physiology Clinical Management Data Development Diagnosis Disease Endothelium Excision Extravasation Functional disorder Genetic Growth Human Immune Evasion Immune checkpoint inhibitor Immunodeficient Mouse Immunosuppression Immunotherapy 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 Prognostic Marker Receptor Protein-Tyrosine Kinases Regulation Resistance Role Sampling Signal Transduction Signaling Molecule T cell infiltration T-Lymphocyte TIE-2 Receptor Testing Therapeutic Time Tumor Escape Tumor Markers Up-Regulation Vascular remodeling Work antagonist anti-PD1 therapy cancer biomarkers checkpoint therapy follow-up high risk immune cell infiltrate immunoregulation improved insight liver function mouse model objective response rate potential biomarker prognostic receptor response therapeutic target transcriptome sequencing tumor tumor diagnosis tumor growth tumor progression tumor-immune system interactions

项目摘要

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.

标题：Angiopoietin-2/Tie2信号对胰腺神经内分泌肿瘤肝转移的调节项目概要近一半的 PanNET 患者在诊断时发现肝转移，而许多其他患者则出现肝转移手术切除原发肿瘤后发生转移。尽管胰腺神经内分泌疾病的发病率近几十年来，肿瘤（PanNET）稳步增长，但治疗选择有限转移性 PanNET 患者。此外，免疫检查点抑制剂（ICI）在治疗中表现出有限的功效。由于免疫抑制微环境而患有转移性 PanNET 的患者。因此，了解肝转移、免疫逃避的机制及其对 ICI 治疗耐药性的影响 PanNET 迫切需要改善先进 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。血管生成素-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 信号传导并促进血管不稳定和泄漏。重要的是，新出现的证据表明血管不稳定会促进通过损害免疫细胞浸润来逃避肿瘤免疫。在初步研究中使用自发在 PanNET 小鼠模型中，我们发现 Ang2 抑制可抑制肝转移生长并改善生存。 Ang2 抑制还减少了血管渗漏并增加了转移灶中 CD8+ T 细胞的浸润。我们之前表明，Tie2 信号传导的抑制伴随着 Tie2 的胞外域裂解辅助受体 Tie1，导致可溶性 Tie1 (sTie1) 的循环水平增加。我们的初步研究表明 PanNET 患者血浆 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，转移性 PanNET 中的免疫抑制和抗 PD-1 治疗耐药性。在目标 1 中，我们将确定 Ang2介导的血管不稳定对PanNET中肝转移进展的贡献人类肝转移和功能阻断抗体或自发性和实验性 PanNET 小鼠模型。从机制上讲，在目标 2 中，我们将确定 Ang2 是否介导血管渗漏损害肝转移灶中 CD8+ T 细胞浸润，可作为评估肝转移灶的基础 Ang2 抑制联合抗 PD-1 治疗对转移性 PanNET 的影响。我们将确定 Ang2 是否阻断通过促进血管稳定和增强 PanNET 肝转移对抗 PD-1 治疗的敏感性 PanNET 小鼠中 CD8+ T 细胞浸润。最后，目标 3 将确定诊断时 sTie1 的循环水平，作为 PanNET 患者肿瘤侵袭性的潜在生物标志物。该项目的顺利完成，阐明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，并为转移性肿瘤的治疗提供见解源自其他肿瘤类型的疾病，尤其是那些对 ICI 治疗反应不佳的肿瘤。