Role of the collagen receptor LAIR-1 in glioma progression and the tumor immune microenvironment

胶原蛋白受体LAIR-1在神经胶质瘤进展和肿瘤免疫微环境中的作用

基本信息

批准号：
10581659
负责人：
Pedro R Lowenstein
金额：
$ 39.73万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581659
关键词：
Affect Affinity B-Lymphocytes Behavior Binding Biochemical Bone Marrow Brain Neoplasms CD8-Positive T-Lymphocytes Cell-Mediated Cytolysis Cells Collagen Collagen Receptors Complex DDR1 gene DDR2 gene Down-Regulation Excision Extracellular Matrix Genetically Engineered Mouse Glioblastoma Glioma Goals Human ITIM Immune Immune response Immunity Immunoglobulin Domain Immunoglobulins In Vitro Infiltration Integrins Invaded Leukocytes Macrophage Malignant - descriptor Malignant Neoplasms Malignant neoplasm of cervix uteri Mediating Membrane Glycoproteins Microglia Modeling Natural Killer Cells Outcome Pathogenesis Pathologic Patients Phenotype Play Primary Brain Neoplasms Radiation therapy Receptor Protein-Tyrosine Kinases Recurrent tumor Renal carcinoma Role Signal Pathway Signal Transduction Solid Neoplasm T-Lymphocyte Testing Therapeutic Therapeutic Effect Tissues Translations Treatment Efficacy Tumor Cell Invasion Tumor Immunity angiogenesis anti-tumor immune response brain tissue cancer cell chemotherapy cytotoxic cytotoxicity discoidin receptor extracellular immune activation immune cell infiltrate in vivo knock-down leukocyte activation malignant breast neoplasm migration monocyte neoplastic cell neuropathology new therapeutic target receptor response standard of care tumor tumor behavior tumor growth tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

ABSTRACT High-grade gliomas (HGG) are the deadliest of all primary brain tumors. They are incurable and median survival is between 18-24 months. Gliomas infiltrate the healthy brain tissue surrounding the tumor. Thus, even if these tumors do not metastasize, patients die due to local tumor recurrence. Collagens are a central component of the extracellular matrix of high-grade gliomas, and promote invasion and tumor growth. How they do so is complex, and not fully understood. Collagen provides structural stiffness to the extracellular matrix, through physical mechanisms. In addition to physical mechanisms, biochemically collagen affects intracellular mechanisms. Collagen affects intracellular signaling by interacting with a large number of collagen receptors. These receptors are: integrins, discoidin domain receptors DDR1 and DDR2, GPVI, MRC2 and LAIR-1. Leukocyte-associated immunoglobulin-like receptor-1 (LAIR- 1) is a transmembrane glycoprotein, its extracellular segment contains a single immunoglobulin-like (Ig- like) domain, and its intracellular segment has two immuno- receptor tyrosine- based inhibitory motifs (ITIMs). LAIR-1 is strongly expressed on T cells, B cells, natural killer (NK) cells, macrophages and other immune cells. LAIR-1 strongly suppresses immune cell activation, thus reducing immune responses. Collagen-rich tumors, especially collagens I and III activate LAIR-1 in CD8+ T cells, and reduce T cell-mediated cytotoxicity. Thus, activation of LAIR-1 on immune cells has been proposed as a mechanism by which tumors inhibit antitumor immune responses. Surprisingly, we found that LAIR-1 is also expressed in glioma cells. Expression of LAIR-1 in other solid tumors, such as cervical, breast and kidney cancer increases tumor aggressiveness. Thus, we postulate that LAIR-1 could affect glioma progression by directly increasing the pathogenesis of cancer cells, and indirectly, by inhibiting the anti-tumor cytotoxic immune responses. Knockdown of collagen from genetically engineered mouse models of glioma increased median survival, and reduced LAIR-1 expression within brain tumors. Thus, collagen could directly inhibit anti-glioma immune responses, or affect the malignant behavior of glioma cells. There is thus a critical need for a mechanistic understanding of how LAIR-1 expressed by either infiltrating immune cells or glioma tumor cells contributes to glioma progression and invasion and how it remodels the tumor immune microenvironment. Our long-term goal is to understand how the extracellular tumor matrix, through its expression of collagen affects tumor progression and anti-tumor immunity. Our overall objectives in this application are to test the hypothesis that LAIR-1 expression in glioma cells increases tumor progression (AIM 1), the role of LAIR-1 expression in regulating the function of infiltrating immune cells (AIM 2), and determine the therapeutic potential of the inhibition of LAIR-1 in glioma models (AIM 3). Our central hypothesis is that LAIR-1 plays essential pathological roles that contribute to glioma progression through its expression in glioma cells and in immune cells and that inhibiting LAIR-1 signaling could uncover novel therapeutic targets for HGG.

抽象的高级神经胶质瘤（HGG）是所有原发性脑肿瘤中最致命的。他们是无法治愈的，中位生存在18-24个月之间。神经胶质瘤浸润肿瘤周围的健康脑组织。因此，即使这些肿瘤不会转移，患者由于局部肿瘤复发而死亡。胶原是高级神经胶质瘤的细胞外基质，并促进侵袭和肿瘤生长。他们的工作方式很复杂，并且没有完全理解。胶原蛋白通过物理为细胞外基质提供结构刚度机制。除了物理机制外，生化胶原蛋白还会影响细胞内机制。胶原蛋白通过与大量胶原蛋白受体相互作用来影响细胞内信号传导。这些受体为：整联蛋白，盘状结构域受体DDR1和DDR2，GPVI，MRC2和LAIR-1。白细胞相关免疫球蛋白样受体-1（Lair-1）是跨膜糖蛋白，其细胞外段包含A 单个免疫球蛋白样（Ig-lik）结构域，其细胞内段具有两个免疫受体酪氨酸 - 基于抑制基序（ITIMS）。 Lair-1在T细胞，B细胞，天然杀伤（NK）细胞上强烈表达，巨噬细胞和其他免疫细胞。 Lair-1强烈抑制免疫细胞活化，从而减少免疫反应。富含胶原蛋白的肿瘤，尤其是胶原蛋白I和III激活CD8+ T细胞中的Lair-1，以及降低T细胞介导的细胞毒性。因此，已经提出了lair-1在免疫细胞上的激活肿瘤抑制抗肿瘤免疫反应的机制。令人惊讶的是，我们发现Lair-1也是在神经胶质瘤细胞中表达。 Lair-1在其他实体瘤中的表达，例如宫颈，乳腺癌和肾癌增加肿瘤的侵略性。因此，我们假设Lair-1可能会直接影响神经胶质瘤的进展通过抑制抗肿瘤的细胞毒性免疫来增加癌细胞的发病机理，并间接增加回答。胶质瘤的基因工程小鼠模型中位数敲低胶原蛋白生存率和脑肿瘤中的Lair-1表达降低。因此，胶原蛋白可以直接抑制抗神经瘤免疫反应或影响神经胶质瘤细胞的恶性行为。因此，对机械的迫切需要了解如何通过浸润免疫细胞或神经胶质瘤肿瘤细胞表达的Lair-1有助于神经胶质瘤的进展和侵袭以及它如何重塑肿瘤免疫微环境。我们的长期目标是为了了解细胞外肿瘤基质如何通过其胶原蛋白的表达影响肿瘤进展和抗肿瘤免疫。我们在本应用程序中的总体目标是检验Lair-1的假设神经胶质瘤细胞中的表达增加了肿瘤的进展（AIM 1），Lair-1表达在调节浸润免疫细胞的功能（AIM 2），并确定lair-1抑制的治疗潜力神经瘤模型（AIM 3）。我们的中心假设是Lair-1扮演着重要的病理作用通过其在神经胶质瘤细胞和免疫细胞中的表达进行胶质瘤进展，并抑制Lair-1 信号传导可能会发现HGG的新型治疗靶标。