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

项目摘要/摘要 程序性细胞死亡1(PD-1)及其配体PD-L1和PD-L2在人和小鼠中高度表达 胸腺。尽管如此，PD-1信号通路在T细胞发育过程中的功能一直是 严重不足的研究。在过去的十年中，抑制PD-1：PD-L1轴的免疫疗法产生了 几种恶性肿瘤临床治疗的显著改善，至少部分是通过恢复T细胞 免疫抑制肿瘤微环境中的受体(TCR)信号。然而，因为TCR 信号对胸腺细胞的发育至关重要，我们推测PD-1/PD-L1抑制剂可能具有深远的影响 新生成的T细胞的功能和特异性。这些特定于胸腺的动作可能会突出一个关键 PD-1阻断诱导抗肿瘤免疫反应的机制尚不清楚。利用这条途径 对于儿童癌症患者来说，考虑到他们胸腺T细胞的高生成率，这种药物可能特别有益。 我们的初步数据表明，造血干细胞(HSCs)与抗PD-1联合使用 治疗扩大了T细胞库，并帮助克服了小鼠胶质母细胞瘤的治疗耐药性。今年5月 提示抗PD-1治疗在胸腺内发挥作用，促进HSC来源的增殖和成熟 胸腺细胞。重要的是，儿童高级别胶质瘤(HGG)是#年癌症相关死亡的主要原因。 它强调了新疗法的必要性。因此，研究这一新的途径是我们的首要任务 目标是提高儿童HGG和其他儿童肿瘤的护理标准。我们的目标是 研究抑制PD-1信号如何改变健康和HGG患者的胸腺细胞发育。中环 这一建议的假设是PD-1抑制增加胸腺T细胞的产生并促进阳性 肿瘤特异性TCR的选择或存活。目标1将确定PD-1封锁对 健康和胶质瘤荷瘤小鼠发育中胸腺细胞的增殖、选择和输出。目标2将 在PD-1抑制剂和肝星状细胞的背景下评估胸腺对治疗反应的贡献 调职。这项工作很有意义，因为以前没有研究过胸腺特异性PD-1是如何被阻断的 影响抗肿瘤免疫反应。这项研究的结果有可能对 儿童HGG患者的临床决策和治疗方案。这个项目具有创新性，因为 它将利用非转基因小鼠模型来更准确地定义PD-1抑制如何影响胸腺 健康和疾病中的生理学。总而言之，这项提案将全面描述PD-1 途径调节T细胞发育，并将研究一种新的胸腺机制，可能会带来革命性的 我们对肿瘤抗PD-1治疗的理解。

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.