Myct1 control of the angioimmune interface

Myct1 控制血管免疫界面

• 批准号: 10681090
• 负责人: KYUNGHEE CHOI
• 金额: $ 55.94万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-09 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681090
• 关键词: Address; Adherens Junction; Adhesions; Angiogenesis Inhibitors; Antibodies; Apoptosis; Binding Proteins; Blood; Blood Vessels; CD8-Positive T-Lymphocytes; CDH5 gene; Cancer Control; Cancer Patient; Cell Adhesion; Cell Adhesion Molecules; Cell membrane; Cells; Cellular biology; Complex; Cytotoxic T-Lymphocytes; Data; Defect; Disease; Embryonic Development; Endothelial Cells; Endothelium; Genes; Genetic; Goals; High Endothelial Venule; Human; Hypoxia; Immune; Immune response; Immune system; Immunity; Investigation; KDR gene; Knock-out; Knockout Mice; Link; Macrophage; Malignant Neoplasms; Membrane Proteins; Modality; Molecular; Monoclonal Antibodies; Mus; Outcome; Output; Pathologic; Pathway interactions; Perfusion; Permeability; Phase; Phosphorylation; Play; Property; Proteins; Proteomics; Regulation; Reporting; Role; Small Interfering RNA; Solid Neoplasm; Structure; T cell infiltration; T-Lymphocyte; Testing; Therapeutic; Tight Junctions; Tissues; Tumor Angiogenesis; Tumor Immunity; angiogenesis; anti-PD-1; anti-PD1 antibodies; cancer therapy; cell motility; comparison control; cytotoxic CD8 T cells; effective therapy; efficacy evaluation; immune checkpoint blockade; improved; knock-down; member; migration; novel; novel therapeutics; overexpression; programmed cell death protein 1; recruit; rho GTP-Binding Proteins; single-cell RNA sequencing; translational potential; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

ABSTRACT Endothelial cells (ECs) form an essential part of the vasculature and are strategically located between blood and tissues, functioning as a fundamental barrier between the tissue and the immune system. As such, ECs can be viewed as an essential and active component regulating immune responses. We propose that EC's angiogenic vs. immune-modulatory function can be linked through the same genetic mechanism. We recently reported that Myct1 (MYC target 1), encoding a plasma membrane protein, is a novel regulator of angiogenesis. Myct1 expression is mainly restricted to ECs and tumor ECs. Global and EC-specific (Cdh5-Cre; Myct1f/f) Myct1 KO mice display decreased tumor angiogenesis and reduced tumor growth. Unexpectedly, defective tumor angiogenesis leads to an anti-tumor immune microenvironment. Particularly, tumors from Myct1 KO mice contain more CD8+ cytotoxic T lymphocytes (CTLs) than tumors from littermate control mice. While Myct1 deficient ECs display defects in EC motility, they support more robust CD8+ T cell trans-endothelial migration (TEM). Importantly, analysis of human cancers has also identified MYCT1 as a modulator of cancer patients' angiogenic and immune outcomes. Inhibition of Myct1 through knockout, siRNA treatment, or blocking monoclonal antibodies, in combination with anti-PD1 antibody, significantly improved complete tumor regression, suggesting that the better control of cancer depends on reduced angiogenesis and enhanced recruitment of CD8+ CTLs. We identified that Myct1 could control the outcome of angiogenesis vs. CTL recruitment to tumors through Rhoa vs. Rac1 Rho GTPase pathways. Moreover, we identified ZO1, also known as tight junction protein 1, to associate with MYCT1. Deeper mechanistic investigations on the Myct1-Rho GTPases and MYCT1-ZO1 interaction will help better understand how ECs control angiogenesis vs. immunity. As Myct1 function is conserved between mice and humans, findings from the proposed studies have high translational potential and can be applied to human anti-cancer therapies. The overall goal is to uncover novel molecular mechanisms and functions of MYCT1 in ECs and anti-tumor immunity. Particularly, we will test the hypothesis that Myct1 can modulate EC angiogenesis vs. immune regulatory outcome. Aim 1 determines how Myct1-Rho GTPase regulates tumor angiogenesis vs. tumor immunity. Aim 2 investigates the functional significance of MYCT1-ZO in EC permeability and vessel integrity. Aim 3 is to further assess the efficacy of anti-MYCT1 antibodies for targeting MYCT1 in tumor angiogenesis and growth. By completing the proposed studies, we will gain a deeper mechanistic understanding of how Myct1 regulates angiogenesis and the consequence of immune output played by ECs. The outcome will significantly impact the basic EC biology and therapeutic modality for cancer treatment.

抽象的 内皮细胞（EC）构成了脉管系统的重要组成部分，在血液和 组织，充当组织和免疫系统之间的基本障碍。因此，EC可以是 被视为调节免疫反应的必不可少的积极成分。我们建议EC的血管生成 可以通过相同的遗传机制将与免疫调节功能与免疫调节功能联系起来。我们最近报道了 编码质膜蛋白的MyCT1（MYC靶标1）是一种新型的血管生成调节剂。 myct1 表达主要局限于EC和肿瘤EC。全球和EC特异性（CDH5-CRE; myct1f/f）myct1 ko 小鼠显示肿瘤血管生成减少，肿瘤生长降低。出乎意料的是，肿瘤有缺陷 血管生成导致抗肿瘤免疫微环境。特别是，来自MyCT1 KO小鼠的肿瘤包含 与窝窝对照小鼠的肿瘤相比，CD8+细胞毒性T淋巴细胞（CTL）多。而MyCT1不足ECS 在EC运动中显示缺陷，它们支持更健壮的CD8+ T细胞反内层迁移（TEM）。 重要的是，对人类癌症的分析还确定了MyCT1是癌症患者血管生成的调节剂 和免疫结果。通过敲除，siRNA处理或阻塞单克隆抑制MyCT1 抗体结合抗PD1抗体，显着改善了完整的肿瘤回归，表明 对癌症的更好控制取决于血管生成减少和CD8+ CTL的募集增强。 我们确定MyCT1可以控制通过RhoA的血管生成与CTL募集到肿瘤的结果 与Rac1 Rho GTPase途径。此外，我们确定了ZO1，也称为紧密连接蛋白1， 与myct1交往。对MYCT1-RHO GTPases和MyCT1-ZO1的更深入的机械调查 相互作用将有助于更好地了解ECS如何控制血管生成与免疫力。因为myct1函数是 小鼠与人之间保守的，拟议研究的发现具有很高的翻译潜力， 可以应用于人类的抗癌疗法。总体目标是发现新颖的分子机制和 MYCT1在EC和抗肿瘤免疫中的功能。特别是，我们将测试MyCt1可以的假设 调节EC血管生成与免疫调节结果。 AIM 1确定MYCT1-RHO GTPase的方式 调节肿瘤血管生成与肿瘤免疫。 AIM 2研究MYCT1-ZO的功能意义 在EC渗透性和血管完整性中。 AIM 3是进一步评估抗Myct1抗体的功效 针对MyCT1在肿瘤血管生成和生长中。通过完成拟议的研究，我们将获得更深入的研究 对MYCT1如何调节血管生成和免疫输出的后果的机械理解 由ECS。结果将显着影响癌症治疗的基本EC生物学和治疗方式。