Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina.
Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois.
Clin Cancer Res. 2023 Dec 1;29(23):4973-4989. doi: 10.1158/1078-0432.CCR-23-0834.
Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan.
Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy.
Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice.
This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.
胶质母细胞瘤（GBM）是成年人中最常见的侵袭性原发性恶性脑肿瘤，发病中位年龄为 68 至 70 岁。尽管年龄较大通常与 GBM 患者生存较差相关，但导致适应性衰老效应的主要来源仍有待确定。在这里，我们研究了全生命周期内患有 GBM 的成年患者的肿瘤内和肿瘤外组织与患有脑瘤的小鼠之间的关系。
在西北医学和 NCI SEER 数据库中评估了电子健康记录中的 GBM 患者年龄和总生存期。商业 Tempus 和 Caris 数据库以及癌症基因组图谱（TCGA）根据 GBM 患者的不同年龄进行了基因表达、DNA 甲基化和突变变化的分析。此外，还对年轻和年老成年小鼠的肿瘤外脑组织进行了基因表达分析，这些小鼠有无脑瘤。在接受或不接受衰老细胞疗法和/或免疫疗法治疗后，评估了携带脑瘤的年轻和年老野生型或转基因（INK-ATTAC）小鼠的存活情况。
年龄≥65 岁的 GBM 患者的生存时间明显短于年龄较小的患者。虽然年轻和年老 GBM 患者的肿瘤内分子谱相似，但患有脑瘤的年轻和年老小鼠的非肿瘤脑组织的基因表达谱存在显著差异，消除衰老细胞可改善免疫治疗依赖性年老小鼠的生存，但对年轻小鼠没有影响。
这项工作表明，在老年 GBM 患者中联合使用衰老细胞疗法和免疫疗法可能具有潜在的益处。
