Thymic PD-1 blockade mediates the anti-tumor immune response in pediatric high-grade glioma

项目总结/摘要 程序性细胞死亡1（PD-1）及其配体PD-L1和PD-L2在人和鼠中高度表达， 胸腺尽管有这些知识，PD-1信号通路在T细胞发育过程中的功能仍不清楚。 严重不足。在过去的十年中，抑制PD-1：PD-L1轴的免疫疗法已经产生了 在几种恶性肿瘤的临床管理方面取得了显着改善，至少部分是通过恢复T细胞 免疫抑制性肿瘤微环境内的TCR信号传导。由于TCR 信号传导对胸腺细胞发育至关重要，我们假设PD-1/PD-L1抑制剂可能具有深远的影响 新产生的T细胞的功能和特异性。这些特定于胸腺的行为可能突出了一个关键 PD-1阻断剂激发抗肿瘤免疫应答的机制尚未探索。利用这一途径 对于儿科癌症患者，考虑到他们的胸腺T细胞产生率高，可能特别有益。 我们的初步数据表明，造血干细胞（HSC）与抗PD-1联合给药， 治疗扩大了T细胞库，并有助于克服鼠胶质母细胞瘤的治疗抗性。这可能 提示抗PD-1治疗在胸腺内起作用，以促进HSC衍生的造血干细胞的增殖和成熟。 胸腺细胞重要的是，儿童高级别胶质瘤（HGG）是儿童癌症相关死亡的主要原因。 强调了新疗法的必要性。因此，研究这一新途径是我们的首要任务 目的是提高儿童HGG和其他儿童肿瘤的护理标准。我们的目标是 表征抑制PD-1信号传导如何改变健康和HGG中的胸腺细胞发育。中央 该提议的假设是PD-1抑制增加胸腺T细胞产生并促进阳性T细胞增殖。 肿瘤特异性TCR的选择或存活。目标1将确定PD-1阻断对肿瘤细胞的影响。 增殖，选择，和输出的发展胸腺细胞在健康和神经胶质瘤荷瘤小鼠。目标2将 评估胸腺对PD-1受体和HSC背景下治疗反应的贡献 转移这项工作是重要的，因为没有先前的研究调查了胸腺特异性PD-1阻滞剂是如何作用的。 影响抗肿瘤免疫反应。这项研究的结果有可能大大影响 儿科HGG患者的临床决策和治疗方案。该项目具有创新性，因为 它将利用非转基因小鼠模型来更准确地确定PD-1抑制如何影响胸腺 健康和疾病的生理学。总之，该提案将全面表征PD-1如何 通路调节T细胞发育，并将研究一种新的胸腺机制， 我们对抗PD-1治疗癌症的理解。

Project Summary/Abstract Programmed cell death 1 (PD-1) and its ligands, PD-L1 and PD-L2, are highly expressed in human and murine thymus. Despite this knowledge, the function of the PD-1 signaling pathway during T cell development has been severely understudied. In the past decade, immunotherapies inhibiting the PD-1:PD-L1 axis have produced remarkable improvements in the clinical management of several malignancies, at least in part by restoring T cell receptor (TCR) signaling within the immunosuppressive tumor microenvironment. However, because TCR signaling is essential for thymocyte development, we postulate PD-1/PD-L1 inhibitors may have profound effects on the function and specificity of newly generated T cells. These thymus-specific actions may highlight a key unexplored mechanism by which PD-1 blockade elicits anti-tumor immune responses. Leveraging this pathway for pediatric cancer patients may be particularly beneficial considering their high rate of thymic T cell production. Our preliminary data illustrate that hematopoietic stem cells (HSCs) administered in conjunction with anti-PD-1 therapy expands the T cell pool and helps overcome treatment-resistance in murine glioblastoma. This may suggest anti-PD-1 therapy acts within the thymus to promote the proliferation and maturation of HSC-derived thymocytes. Importantly, pediatric high-grade glioma (HGG) is the prevailing cause of cancer-related death in children which emphasizes the need for new therapies. Thus it is our priority to investigate this novel pathway with the goal of improving the standard of care for pediatric HGG and other childhood tumors. Our objective is to characterize how inhibiting PD-1 signaling modifies thymocyte development in health and HGG. The central hypothesis of this proposal is that PD-1 inhibition increases thymic T cell production and promotes the positive selection, or survival, of tumor-specific TCRs. Aim 1 will determine the impact of PD-1 blockade on the proliferation, selection, and output of developing thymocytes in healthy and glioma-bearing mice. Aim 2 will assess the thymic contribution towards the therapeutic response in the context of PD-1 inhibiton and HSC transfer. This work is significant because no prior study has investigated how thymus-specific PD-1 blockade impacts anti-tumor immune responses. The results from this study have the potential to substantially influence clinical decision making and treatment regimens for pediatric HGG patients. This project is innovative because it will utilize nontransgenic mouse models to more accurately define how PD-1 inhibition affects thymus physiology in health and disease. In summary this proposal will comprehensively characterize how the PD-1 pathway modulates T cell development and will investigate a novel thymic mechanism that may revolutionize our understanding of anti-PD-1 therapy in cancer.