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.

摘要 内皮细胞（EC）形成脉管系统的重要部分，并且策略性地位于血液和血管之间。 组织，作为组织和免疫系统之间的基本屏障。因此，EC可以是 被认为是调节免疫反应的必要和活性成分。我们认为EC的血管生成 vs.免疫调节功能可以通过相同的遗传机制联系起来。我们最近报道说， Myct 1（MYC target 1）编码一种质膜蛋白，是一种新的血管生成调节因子。Myct1 表达主要限于EC和肿瘤EC。全局和EC特异性（Cdh 5-Cre; Myct 1f/f）Myct 1 KO 小鼠显示出降低的肿瘤血管生成和降低的肿瘤生长。出乎意料的是，缺陷肿瘤 血管生成导致抗肿瘤免疫微环境。特别地，来自Myct 1 KO小鼠的肿瘤含有 与同窝对照小鼠的肿瘤相比，CD 8+细胞毒性T淋巴细胞（CTL）更多。而Myct 1缺陷的EC 尽管它们显示EC运动性的缺陷，但它们支持更稳健的CD 8 + T细胞跨内皮迁移（TEM）。 重要的是，对人类癌症的分析也已经确定MYCT 1是癌症患者血管生成的调节剂。 免疫结果。通过敲除、siRNA处理或阻断单克隆抗体抑制Myct 1 抗PD 1抗体与抗PD 1抗体联合显著改善了肿瘤的完全消退，表明 更好地控制癌症取决于减少血管生成和增强CD 8 + CTL的募集。 我们发现Myct 1可以通过Rhoa调控肿瘤血管生成和CTL募集的结果。 vs. Rac 1 Rho GT3通路。此外，我们鉴定了ZO 1，也称为紧密连接蛋白1， 与MYCT 1关联。Myct 1-Rho GTP酶和MYCT 1-ZO 1的深入机制研究 相互作用将有助于更好地理解EC如何控制血管生成与免疫。由于Myct 1函数是 在小鼠和人类之间是保守的，来自拟议研究的发现具有很高的翻译潜力， 可用于人类抗癌治疗。总体目标是揭示新的分子机制， MYCT 1在内皮细胞和抗肿瘤免疫中的作用。特别地，我们将测试Myct 1可以 调节EC血管生成与免疫调节结果。Aim 1确定Myct 1-Rho GTPase如何 调节肿瘤血管生成与肿瘤免疫。目的2探讨MYCT 1-ZO的功能意义 EC渗透性和血管完整性。目的3是进一步评估抗MYCT 1抗体对治疗糖尿病的功效。 靶向MYCT 1在肿瘤血管生成和生长中的作用。通过完成拟议的研究，我们将获得更深入的 对Myct 1如何调节血管生成和免疫输出结果的机制理解 的EC。结果将显著影响癌症治疗的基本EC生物学和治疗方式。