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The CD93 pathway and melanoma therapy

CD93 通路和黑色素瘤治疗

基本信息

批准号：
10364508
负责人：
Yuwen Zhu
金额：
$ 35.57万
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/10364508
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 Exclusion Extravasation Feedback Functional disorder Genes Goals Human Hypoxia Image Immune Immunologics Immunotherapy Infiltration KDR gene Ligands 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-Lymphocyte Testing Therapeutic Time Tissues Toxic effect Tumor Tissue Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Up-Regulation Vascular Diseases Vascular Endothelial Growth Factors Vegf Inhibitor anti-PD-1 anti-PD1 therapy cancer immunotherapy cancer therapy cancer type 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

项目总结/文摘