Advanced Age Increases Immunosuppression in the Brain and Decreases Immunotherapeutic Efficacy in Subjects with Glioblastoma.
Advanced Age Increases Immunosuppression in the Brain and Decreases Immunotherapeutic Efficacy in Subjects with Glioblastoma.
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DOI：
10.1158/1078-0432.ccr-19-3874
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发表时间：
2020-10-01
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影响因子：
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通讯作者：
Wainwright DA
中科院分区：
文献类型：
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作者：
Ladomersky E;Zhai L;Lauing KL;Bell A;Xu J;Kocherginsky M;Zhang B;Wu JD;Podojil JR;Platanias LC;Mochizuki AY;Prins RM;Kumthekar P;Raizer JJ;Dixit K;Lukas RV;Horbinski C;Wei M;Zhou C;Pawelec G;Campisi J;Grohmann U;Prendergast GC;Munn DH;Wainwright DA
野生型表达异柠檬酸脱氢酶的胶质母细胞瘤（GBM）是最常见和侵袭性的原发性脑肿瘤，诊断时的中位年龄≥65岁。它占所有GBM的约90%，中位总生存期(OS) <15个月。尽管免疫检查点疗法在多种侵袭性恶性肿瘤中取得了显著的生存效益，但迄今为止，在GBM的III期临床试验中尚未取得类似的成功。我们的研究旨在了解受试者年龄和免疫治疗效果之间的关系，因为它关系到胶质瘤的生存。1)临床数据：来自肿瘤基因组图谱、西北医学企业数据仓库和评估免疫检查点阻断（ICB）的临床研究的胶质母细胞瘤患者数据集按年龄分层，并对OS进行比较。2)动物模型：在脑内植入CT-2A或GL261胶质瘤细胞系，用或不用CTLA-4/PD-L1单抗或放射、抗pd -1单抗和/或药理学IDO酶抑制剂治疗年轻、中年和老年成年野生型和IDO敲除同基因小鼠。高龄与GBM患者生存率降低相关，与ICB治疗无关。老年相关的脑IDO表达增加与免疫治疗效果的抑制有关，并且IDO酶抑制剂治疗不能逆转。老年时大脑免疫抑制增加，并抑制老年人抗胶质瘤免疫。展望未来，充分了解老年脑内导致老年GBM患者在ICB治疗期间生存率下降的因素和机制将是非常重要的。
Wild-type isocitrate dehydrogenase-expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for ~90% of all GBM and has a median overall survival (OS) of <15 months. Although immune checkpoint therapy has achieved remarkable survival benefits in a variety of aggressive malignancies, similar success has yet to be achieved for GBM among phase III clinical trials to-date. Our study aimed to understand the relationship between subject age and immunotherapeutic efficacy as it relates to survival from glioma. 1) Clinical data: Glioblastoma patient datasets from the cancer genome atlas, Northwestern Medicine Enterprise Data Warehouse, and clinical studies evaluating immune checkpoint blockade (ICB) were stratified by age and compared for OS. 2) Animal models: Young, middle-aged and older adult wild-type and IDO knock-out syngeneic mice were intracranially-engrafted CT-2A or GL261 glioma cell lines and treated with or without CTLA-4/PD-L1 mAbs, or radiation, anti-PD-1 mAb and/or a pharmacologic IDO enzyme inhibitor. Advanced age was associated with decreased GBM patient survival regardless of treatment with ICB. The advanced age-associated increase of brain IDO expression was linked to the suppression of immunotherapeutic efficacy and was not reversed by IDO enzyme inhibitor treatment. Immunosuppression increases in the brain during advanced age and inhibits anti-glioma immunity in older adults. Going-forward, it will be important to fully understand the factors and mechanisms in the elderly brain that contribute to the decreased survival of older GBM patients during treatment with ICB.