The CD93 pathway and melanoma therapy

CD93 通路和黑色素瘤治疗

基本信息

批准号：
10534230
负责人：
Yuwen Zhu
金额：
$ 34.86万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-03 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10534230
关键词：
Angiogenic Factor Binding Biological Blocking Antibodies Blood Vessels CD8-Positive T-Lymphocytes CD8B1 gene Cell Adhesion Molecules Cells Clinical Confocal Microscopy Drug Delivery Systems Endothelium Exclusion Extravasation Feedback Functional disorder Genes Goals Human Hypoxia Image Immune Immunologics Immunotherapy Infiltration KDR gene Ligands Lymphocyte Function Lymphocytic Infiltrate Malignant Neoplasms Modeling Molecular Monoclonal Antibodies Mus Myeloid-derived suppressor cells Neoplasm Metastasis Neoplasms in Vascular Tissue Outcome PD-1 inhibitors PD-1/PD-L1 Pathway interactions Patients Perfusion Physiologic Neovascularization Relapse Research Resistance Role Shapes Signal Transduction Specimen T cell infiltration T-Lymphocyte Testing Therapeutic Tissues Toxic effect Tumor Tissue Tumor-Infiltrating Lymphocytes Up-Regulation Vascular Diseases Vascular Endothelial Growth Factors Vegf Inhibitor Visualization anti-PD-1 anti-PD1 therapy cancer immunotherapy cancer therapy cancer type immune cell infiltrate immune checkpoint blockers immune function improved in vivo inhibiting antibody insight melanoma migration novel novel strategies novel therapeutic intervention resistance mechanism therapeutic evaluation tumor tumor growth tumor hypoxia tumor microenvironment tumor-immune system interactions vascular abnormality

项目摘要

PROJECT SUMMARY/ABSTRACT Immune checkpoint blocker therapy has recently greatly improved survival of patients with late- stage melanoma. However, about 2/3 of patients do not benefit from this therapy. One of main hurdles is that many melanoma tissues lack effector CD8+ T cells. The immature and dysfunctional blood vessels actively limit T cell infiltration. Recently vascular normalization has been demonstrated to be able to facilitate effector immune cell infiltration and to improve cancer immunotherapy. a novel pathway in the IGFBP7/CD93 interaction, both of which are selectively upregulated in tumor vasculature. Our preliminary study indicates that disrupting this interaction in vivo normalizes tumor vessels to reduce hypoxia and improve tumor perfusion in mouse melanoma models. Our examination of tumor tissues reveals that blockade of this pathway could reinvigorate tumor blood vessels to promote T cell infiltration while limit myeloid-derived suppressor cells in the tumor. Here we hypothesize that upregulation of this pathway contributes to the tumor vascular abnormality and targeting this pathway will offer a novel approach to facilitate melanoma immunotherapy. We will dissect how this pathway is induced in the tumor and consequently leads to tumor vascular dysfunction and then tumor outgrowth. The mechanisms by which CD93 regulates immune cell infiltration, as well as its expression causing resistance to anti-PD1 therapy, will be evaluated. By the completion of these studies, we will gain insight into the biological role of this pathway in the cancer microenvironment of melanoma and, more importantly, provide a new strategy of promoting immunotherapy in melanoma. Our studies uncovered

项目摘要/摘要免疫检查点阻滞剂治疗最近已大大提高了晚期患者的生存率黑色素瘤。但是，大约2/3的患者无法从这种疗法中受益。主要障碍之一是黑色素瘤组织缺乏效应CD8+ T细胞。未成熟和功能障碍的血管积极限制T 细胞浸润。最近已证明血管归一化能够促进效应子免疫细胞浸润并改善癌症免疫疗法。一条新颖的道路 IGFBP7/CD93相互作用，两者在肿瘤脉管系统中有选择地上调。我们的初步研究表明，在体内破坏这种相互作用可以使肿瘤血管归一化，以减少缺氧并改善。小鼠黑色素瘤模型中的肿瘤灌注。我们对肿瘤组织的检查发现途径可以振兴肿瘤血管以促进T细胞浸润，而限制了髓样衍生的抑制肿瘤中的细胞。在这里，我们假设该途径的上调有助于肿瘤血管异常和靶向这种途径将提供一种新颖的方法来促进黑色素瘤免疫疗法。我们将剖析该途径如何在肿瘤中诱导，从而导致肿瘤血管功能障碍，然后肿瘤生长。 CD93调节免疫细胞的机制将评估浸润及其表达，从而评估引起抗PD1治疗的抵抗力。由完成这些研究，我们将深入了解该途径在癌症中的生物学作用黑色素瘤的微环境，更重要的是，提供了一种促进免疫疗法的新策略黑色素瘤。我们的研究裸露