T Cell Regulation of Low-Grade Glioma

项目摘要 胶质瘤是最常见的脑癌。而恶性胶质瘤多见于成人，低度恶性 脑胶质瘤(LGG)是儿童脑肿瘤的主要类型。虽然LGG通常不是 患有这些肿瘤的幼儿通常有长期的内科疾病，要么是肿瘤 或与传统疗法相关的神经毒性。尤其是对于患有 神经纤维瘤病1型(NF1)癌症易感综合征，近20%的儿童将发展为 LGGs累及视路(视路胶质瘤；OPGs)，可导致视力丧失。目前，治疗方法 对于NF1-LGGs来说，重点在于使用以下两种方法之一来阻止癌细胞的生长： 卡铂/长春新碱)或分子靶向(如MEK抑制剂)治疗，具有不同的持久效果。 重要的是，人NF1-LGGs中30%-50%的细胞是非肿瘤细胞，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)，我们的实验室证明这两种细胞都是必需的 实验性NF1-OPG小鼠模型肿瘤的形成和生长。使用这些NF1-OPG小鼠品系， 我们之前已经定义了一个“神经元免疫癌细胞回路”，在这个回路中，NF1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。具体来说，我们 证实NF1突变的人和小鼠神经元产生中期因子，在体外和 在体内分泌CCL4，然后作用于小胶质细胞诱导CCL5表达，CCL5是 NF1-OPG的形成和生长。令人惊讶的是，我们发现CD8+T细胞在人类和小鼠中都占主导地位 NF1-LGG，其中高CD8水平，而不是CD4水平，与LGG患者总体存活率的降低相关。 此外，我们实验室的研究表明，抗体介导的CD8+T细胞耗尽减少了小鼠NF1- OPG在体内的生长。基于这些发现，我们假设CD8+T细胞在神经元中发挥作用- 免疫癌细胞回路作为免疫球蛋白G发生和发展的固有调节器。为了测试这一点 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) 确定小鼠NF1视神经胶质瘤的免疫成分，(B)确定为什么CD8+T细胞选择性 (C)阐明神经元中NF1突变如何改变T细胞-小胶质细胞 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。 癌细胞轴对LGG形成和生长的调控，关系到未来的发展 免疫调节治疗策略。 OMB编号0925-0001/0002(第03/2020版批准至2023年2月28日)第1页续格式页

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