T Cell Regulation of Low-Grade Glioma

低级别胶质瘤的 T 细胞调节

• 批准号: 10700099
• 负责人: David H Gutmann
• 金额: $ 48.33万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700099
• 关键词: Adult; Affect; Antibodies; Astrocytoma; Blindness; Blood; Brain; Brain Neoplasms; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Cell Growth; Carboplatin; Cell physiology; Cells; Child; Childhood; Childhood Malignant Brain Tumor; Common Neoplasm; Data; Dependence; Development; Etiology; Evolution; Experimental Designs; Flow Cytometry; Future; Gene Mutation; Genetic Transcription; Glioma; Goals; Growth; Growth Factor; Heterozygote; Human; Immune; Immune system; Immunohistochemistry; In Vitro; Individual; Laboratories; Lymphocyte; MEKs; Macrophage; Malignant - descriptor; Malignant Glioma; Malignant neoplasm of brain; Mediating; Medical; Meninges; Microglia; Molecular; Molecular Target; Morbidity - disease rate; Mouse Strains; Mus; Mutant Strains Mice; Mutation; NF1 gene; NF1 mutation; Neoplasms; Neurofibromatosis 1; Neurons; Optic Nerve; Optic Nerve Glioma; Optics; Pathway interactions; Patients; Persons; Population; Population Dynamics; Production; Property; Regulation; Role; Series; Solid Neoplasm; Syndrome; T cell regulation; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; Testing; Tumor-Associated Process; Vincristine; cancer cell; cancer predisposition; cell type; conventional therapy; cytokine; design; experimental study; genotoxicity; immune modulating agents; in vivo; inhibitor; midkine; monocyte; mouse model; mutant; neuronal excitability; neurotoxicity; recruit; single-cell RNA sequencing; tumor

Project Summary Gliomas are the most common brain cancer. Whereas malignant gliomas predominate in adults, low-grade gliomas (LGGs) comprise the majority of brain tumors in the pediatric population. While LGGs are not typically fatal, young children with these neoplasms commonly have long-term medical morbidities, from either the tumor itself or the neurotoxicity associated with conventional therapies. This is particularly true for individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, where nearly 20% of children will develop LGGs involving the optic pathway (optic pathway gliomas; OPGs) that can lead to vision loss. Currently, therapies for NF1-LGGs are focused on arresting the growth of the cancer cells using either genotoxic (e.g., carboplatin/vincristine) or molecularly targeted (e.g., MEK inhibitors) treatments, with variable durable effects. Importantly, 30-50% of the cells in human NF1-LGGs are non-neoplastic cells, such as neurons, lymphocytes (T cells) and monocytic cells (macrophages and microglia), which our laboratory has shown are required for both tumor formation and growth in experimental murine models of Nf1-OPG. Using these Nf1-OPG mouse strains, we have previously defined a “neuron-immune-cancer cell circuit” in which Nf1-mutant neurons activate T cells to produce cytokines that stimulate microglia to support LGG formation and continued growth. Specifically, we demonstrated that NF1-mutant human and murine neurons produce midkine, which activates T cells in vitro and in vivo to secrete Ccl4, which then acts on microglia to induce Ccl5 expression, an essential growth factor for Nf1-OPG formation and growth. Surprisingly, we found that CD8+ T cells predominate in both human and mouse NF1-LGG, where high CD8, but not CD4, levels correlate with reduced overall survival in people with LGG. Moreover, studies in our laboratory revealed that antibody-mediated CD8+ T cell depletion reduces mouse Nf1- OPG growth in vivo. Based on these findings, we hypothesize that CD8+ T cells function in a neuron- immune-cancer cell circuit as obligate modulators of LGG development and progression. To test this hypothesis, we have designed a series of experiments we have designed a series of experiments that aim to (a) define the immune composition of Nf1 optic gliomas in mice, (b) determine why CD8+ T cells are selectively recruited in these murine brain tumors, and (c) elucidate how NF1 mutation in neurons modifies T cell-microglia interactions. Collectively, these studies aim to mechanistically dissect the role of CD8+ T cells in neuron-immune- cancer cell axis regulation of LGG formation and growth, relevant to the development of future immunomodulatory therapeutic strategies. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page 1 Continuation Format Page

项目摘要 神经胶质瘤是最常见的脑癌。恶性胶质瘤在成人中占主导地位， 神经胶质瘤（LGG）构成儿科人群中的大部分脑肿瘤。虽然LGG通常不是 患有这些肿瘤的致命的幼儿通常具有长期的医学发病率， 本身或与传统疗法相关的神经毒性。这对于那些患有 神经纤维瘤病1型（NF 1）癌症易感综合征，其中近20%的儿童将发展 累及视路的LGG（视路胶质瘤; OPG）可导致视力丧失。目前，治疗 对于NF 1-LGG的研究集中于使用基因毒性（例如， 卡铂/长春新碱）或分子靶向（例如，MEK抑制剂）治疗，具有可变的持久效果。 重要的是，人NF 1-LGGs中30-50%的细胞是非肿瘤细胞，如神经元、淋巴细胞 我们的实验室已经证明，T细胞和单核细胞（巨噬细胞和小胶质细胞）是这两种细胞所必需的。 Nf 1-OPG实验鼠模型中的肿瘤形成和生长。使用这些Nf 1-OPG小鼠品系， 我们先前已经定义了一个“神经元-免疫-癌细胞回路”，其中Nf 1突变的神经元激活T细胞 产生刺激小胶质细胞的细胞因子，以支持LGG的形成和持续生长。我们特别 证明NF 1突变的人类和小鼠神经元产生中期因子，其在体外激活T细胞， 在体内分泌Ccl 4，然后作用于小胶质细胞以诱导Ccl 5表达，Ccl 5是一种用于 Nf 1-OPG的形成和生长。令人惊讶的是，我们发现CD 8 + T细胞在人类和小鼠中占主导地位， NF 1-LGG，其中高CD 8，而不是CD 4，水平与LGG患者的总生存率降低相关。 此外，我们实验室的研究表明，抗体介导的CD 8 + T细胞耗竭减少了小鼠Nf 1-T细胞。 体内OPG生长。基于这些发现，我们假设CD 8 + T细胞在神经元中起作用， 免疫癌细胞回路作为LGG发育和进展专性调节剂。为了验证这一 假设，我们设计了一系列实验，我们设计了一系列实验，旨在（a） 确定小鼠中Nf 1视神经胶质瘤的免疫组成，（B）确定为什么CD 8 + T细胞选择性地 在这些小鼠脑肿瘤中招募，以及（c）阐明神经元中的NF 1突变如何修饰T细胞-小胶质细胞 交互.总的来说，这些研究旨在从机制上剖析CD 8 + T细胞在神经元免疫中的作用。 癌细胞轴调节LGG的形成和生长，关系到未来的发展 免疫调节治疗策略。 OMB编号0925-0001/0002（修订版03/2020批准至02/28/2023）第1页续格式第页