Melanoma Immunotherapy with GPR182 blockade

阻断 GPR182 的黑色素瘤免疫疗法

基本信息

批准号：
10585749
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：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585749
关键词：
Ablation Binding Biological Assay CD8-Positive T-Lymphocytes CXCL10 gene CXCL9 gene CXCR3 gene Cell Therapy Cells Characteristics Clinical Endocytosis Endothelial Cells Endothelium Exhibits Extracellular Matrix G-Protein-Coupled Receptors Generations Genetic Glycosaminoglycans Homing Human Image Immune Immune response Immunity Immunologic Sensitization Immunologics Immunotherapy In Vitro Infiltration Inflammation Inflammatory Investigation Leukocytes Ligands Lymphatic Lymphatic Endothelial Cells Malignant Neoplasms Modeling Molecular Monoclonal Antibodies Mus Mutagenesis Orphan Outcome Pathway interactions Patients Peptides Play Positioning Attribute Pre-Clinical Model Publications Refractory Research Proposals Role Stromal Cells T cell infiltration T cell response T-Lymphocyte Techniques Testing Therapeutic Tissues Tumor Immunity anti-tumor immune response antitumor effect cancer immunotherapy cell motility checkpoint therapy chemokine chemokine receptor effector T cell immune cell infiltrate immune checkpoint blockade immune function immunoregulation improved in vivo melanoma migration neoplasm immunotherapy novel novel strategies receptor scavenger receptor targeted cancer therapy tumor tumor growth tumor microenvironment tumor progression two photon microscopy

项目摘要

Project Summary Melanoma immunotherapy with GPR182 blockade Immune checkpoint inhibitor therapy has greatly improved survival of patients with late-stage melanoma. However, over half of patients do not benefit from this therapy. One of the main hurdles is that many melanoma tissues lack effector CD8+ T cell infiltrates. Chemokines such as CXCL9 and CXCL10 play an important role in regulating effector T cell infiltration into the tumors. Atypical Chemokine Receptors are a group of GPCR proteins that are expressed in non-immune cells to actively regulate chemokines by endocytosis. Our studies uncovered GPR182 as a novel ACKR receptor selectively upregulated in peritumoral lymphatics. Our preliminary results indicated that genetic deletion of this molecule in mice led to increased effector T cell infiltration and thereby the retardment of tumor growth in several mouse melanoma models. We further found that GPR182 interacts with chemokines broadly in vitro and blockade of CXCR3 completely abolished improved antitumor immunity in GPR182- deficient mice. Here we hypothesize that GPR182 inhibits anti-tumor immune response by limiting chemokine availability and targeting this pathway offers a novel approach to converting immunologically cold melanoma to hot ones. We will dissect the molecular interaction between GPR182 and chemokines, and also examine the chemokine endocytosis by GPR182 with tumors. The mechanisms by which GPR182 inhibits antitumor T cell response will be investigated. Finally, the in vivo antitumor effect of a GPR182 monoclonal antibody, which blocks the interaction between GPR182 and chemokines, will be assessed. By the completion of these studies, we will identify a new strategy of inflaming immunologically cold melanoma and will have a better understanding of the immunomodulatory role of the lymphatics in melanoma.

项目概要阻断 GPR182 的黑色素瘤免疫疗法免疫检查点抑制剂治疗大大提高了晚期黑色素瘤患者的生存率。然而，超过一半的患者没有从这种疗法中受益。主要障碍之一是许多黑色素瘤组织缺乏效应 CD8+ T 细胞浸润。 CXCL9 和 CXCL10 等趋化因子在调节效应 T 细胞向肿瘤的浸润。非典型趋化因子受体是一组 GPCR 蛋白在非免疫细胞中表达，通过内吞作用主动调节趋化因子。我们的研究发现探地雷达182 作为一种在瘤周淋巴管中选择性上调的新型 ACKR 受体。我们的初步结果表明小鼠体内该分子的基因缺失导致效应 T 细胞浸润增加，从而在几种小鼠黑色素瘤模型中抑制肿瘤生长。我们进一步发现 GPR182 与体外广泛的趋化因子和 CXCR3 的阻断完全消除了改善的抗肿瘤免疫力 GPR182-缺陷小鼠。在这里，我们假设 GPR182 通过限制趋化因子的可用性和针对该途径提供了一种转变免疫冷的新方法黑色素瘤到热的。我们将剖析 GPR182 和趋化因子之间的分子相互作用，并且检查 GPR182 对肿瘤的趋化因子内吞作用。 GPR182 的抑制机制将研究抗肿瘤 T 细胞反应。最后，GPR182单克隆抗体的体内抗肿瘤作用将评估阻断 GPR182 和趋化因子之间相互作用的抗体。到完成时在这些研究中，我们将确定一种炎症免疫冷黑色素瘤的新策略，并将有一个更好地了解淋巴管在黑色素瘤中的免疫调节作用。