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。而恶性神经胶质瘤占成年人，低度 神经胶质瘤（LGGS）包括小儿种群中的大多数脑肿瘤。虽然LGG通常不是 这些肿瘤的致命的年幼儿童通常患有长期医疗病。 本身或与常规疗法相关的神经毒性。对于拥有的人来说，尤其如此 神经纤维瘤病1型（NF1）癌症易感综合征，几乎20％的儿童会发展 涉及光学途径（光学途径胶质瘤； OPG）的LGG可以导致视力丧失。目前，治疗 对于NF1，LGGS专注于使用任何一种遗传毒性来阻止癌细胞的生长（例如， 卡铂/长脂蛋白）或分子靶向（例如MEK抑制剂）处理，具有可变耐用作用。 重要的是，人NF1-LGG中有30-50％的细胞是非肿瘤细胞，例如神经元，淋巴细胞 （T细胞）和单核细胞（巨噬细胞和小胶质细胞），我们的实验室已经表明，这两者都需要 NF1-OPG实验鼠模型的肿瘤形成和生长。使用这些NF1-OPG小鼠菌株， 我们以前已经定义了“神经元 - 免疫癌细胞电路”，其中NF1突变神经元激活T细胞 产生刺激小胶质细胞以支持LGG形成和持续生长的细胞因子。具体来说，我们 证明了NF1突变的人和鼠神经元产生了中胺，该中心在体外激活T细胞， 在体内至秘密CCL4，然后作用于小胶质细胞诱导CCL5表达，这是一个重要的生长因子 NF1-OPG的形成和增长。令人惊讶的是，我们发现CD8+ T细胞在人和小鼠中占主导地位 NF1-LGG，其中高CD8（而不是CD4）水平与LGG患者的总体存活率降低相关。 此外，我们实验室的研究表明，抗体介导的CD8+ T细胞耗竭可减少小鼠NF1-- OPG体内增长。基于这些发现，我们假设CD8+ T细胞在神经元中起作用 免疫接种电池作为LGG发育和进展的强制调节器。测试这个 假设，我们设计了一系列实验，我们设计了一系列实验，目的是（a） 定义小鼠NF1光学胶质瘤的免疫组成，（b）确定CD8+ T细胞为何选择性 在这些鼠脑肿瘤中招募，（c）阐明神经元中的NF1突变如何修饰T细胞 - 神经元 互动。总的来说，这些研究旨在机械地剖析CD8+ T细胞在神经元免疫中的作用 LGG形成和生长的癌细胞轴调节与未来的发展有关 免疫调节治疗策略。 OMB No. 0925-0001/0002（修订版03/2020通过02/28/2023批准）Page 1延续格式页面