缺乏类人髓母细胞瘤模型来模拟人类免疫生物学已经阻碍了基础和翻译免疫学研究。因此，我们开发了来自Nestin-CreERT2QkL/L；Trp53L/L；PtenL/L（QPP）小鼠中的髓母细胞瘤干细胞系，这些小鼠具有人类髓母细胞瘤中常见的临床相关遗传突变。本研究旨在确定这些QPP系在免疫竞争宿主中的免疫敏感性和潜在机制。未处理、抗-PD-1或抗-CTLA-4治疗小鼠的QPP系的不同反应性在大脑和侧面被评估。通过全外显子测序来测量每个肿瘤的反应性对基因组景观的影响。使用流式细胞术比较了QPP7（敏感）与QPP8（耐药）系在大脑中的免疫微环境。还测量了QPP8的敏感的侧面和大脑的驱动因素。QPP系是与C57BL/6J小鼠同基因的，并且对T细胞免疫检查点抑制具有不同的敏感性，从治愈反应到完全耐药。对QPP8的浸润性肿瘤免疫分析揭示了在皮下移植（敏感）时改善的T细胞适应性和增强的效应细胞/抑制细胞比率，在脑部移植时缺乏这些表现（抗药性）。髓样细胞免受免疫攻击的状态在髓母细胞瘤中被PD-L1上调。相反，QPP7即使在大脑中也对检查点免疫疗法做出了反应，这可能是由于其较高的新抗原负担导致的。这些QPP髓母细胞瘤同基因模型展现了临床相关的免疫治疗敏感性和潜在的机制发现和评价免疫治疗的功用。©2023由牛津大学出版社代表神经肿瘤学协会出版。保留所有权利。有关权限，请发送电子邮件至：journals.permissions@oup.com。

The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We therefore developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and underlying mechanisms.The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on responsiveness of each tumor was measured through whole exome sequencing. The immune microenvironments of sensitive (QPP7) versus resistant (QPP8) lines were compared in the brain using flow cytometry. Drivers of flank sensitivity versus brain resistance were also measured for QPP8.QPP lines are syngeneic to C57BL/6J mice and demonstrate varied sensitivities to T cell immune checkpoint blockade ranging from curative responses to complete resistance. Infiltrating tumor immune analysis of QPP8 reveals improved T cell fitness and augmented effector to suppressor ratios when implanted subcutaneously (sensitive), which are absent upon implantation in the brain (resistant). Upregulation of PD-L1 across the myeloid stroma acts to establish this state of immune privilege in the brain. In contrast, QPP7 responds to checkpoint immunotherapy even in the brain likely resulting from its elevated neoantigen burden.These syngeneic QPP models of glioblastoma demonstrate clinically-relevant profiles of immunotherapeutic sensitivity and potential utility for both mechanistic discovery and evaluation of immune therapies.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.