Metabolic Shift Mirrors GBM Immunity to Anti-PD-L1 Immunotherapy: A Deuterium MRS Study.

IF 2.5 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Molecular Imaging and Biology Pub Date : 2025-10-03 DOI:10.1007/s11307-025-02037-w

Joel R Garbow, Xia Ge, Tanner M Johanns, John A Engelbach, Keith M Rich, Joseph J H Ackerman

{"title":"Metabolic Shift Mirrors GBM Immunity to Anti-PD-L1 Immunotherapy: A Deuterium MRS Study.","authors":"Joel R Garbow, Xia Ge, Tanner M Johanns, John A Engelbach, Keith M Rich, Joseph J H Ackerman","doi":"10.1007/s11307-025-02037-w","DOIUrl":null,"url":null,"abstract":"Background/objectives: Immune checkpoint blockade (ICB) therapy has been ineffective in glioblastoma (GBM) that recurs following standard-of-care resection and chemoradiation of the primary tumor. Herein, we investigate whether the delayed effect of intracranial radiation alters the tumor lesion metabolic profile.Methods: Naïve (non-irradiated) GL261 tumor cells were implanted into the brains of C57BL/6 mice. Brains of one cohort were hemispherically irradiated six weeks prior to implantation, ultimately resulting in ICB refractory GBM. Brains of the control cohort were not irradiated. Following subcutaneous infusion of [6,6-2H2] glucose (Glc), single voxel deuterium metabolic imaging (DMI) monitored Glc uptake and the production of semi-heavy water (HOD), 2H2-lactate (Lac) and the 50/50 mix of [2H2-glutamate + 2H2-glutamine] (Glx).Results: GL261 tumors growing in previously irradiated brain showed reduced Warburg effect (aerobic glycolysis; glucose → lactate) and greater TCA cycle activity (respiration, oxidative phosphorylation) relative to tumors growing in non-irradiated brain as evidenced by cohort differences in the ratios Glx/Lac (p < 0.01), Glx/Glc (p < 0.02), and Lac/Glc (p < 0.01).Conclusions: A metabolic program skewed toward oxidative phosphorylation and away from glycolysis has been associated with immune dysfunction. This study documents such a skewed metabolic state in ICB refractory GL261 GBM growing in irradiated brain (tumors were not irradiated) compared to control brain.","PeriodicalId":18760,"journal":{"name":"Molecular Imaging and Biology","volume":" ","pages":""},"PeriodicalIF":2.5000,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Imaging and Biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11307-025-02037-w","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}

引用次数: 0

Abstract

Background/objectives: Immune checkpoint blockade (ICB) therapy has been ineffective in glioblastoma (GBM) that recurs following standard-of-care resection and chemoradiation of the primary tumor. Herein, we investigate whether the delayed effect of intracranial radiation alters the tumor lesion metabolic profile.

Methods: Naïve (non-irradiated) GL261 tumor cells were implanted into the brains of C57BL/6 mice. Brains of one cohort were hemispherically irradiated six weeks prior to implantation, ultimately resulting in ICB refractory GBM. Brains of the control cohort were not irradiated. Following subcutaneous infusion of [6,6-²H₂] glucose (Glc), single voxel deuterium metabolic imaging (DMI) monitored Glc uptake and the production of semi-heavy water (HOD), ²H₂-lactate (Lac) and the 50/50 mix of [²H₂-glutamate + ²H₂-glutamine] (Glx).

Results: GL261 tumors growing in previously irradiated brain showed reduced Warburg effect (aerobic glycolysis; glucose → lactate) and greater TCA cycle activity (respiration, oxidative phosphorylation) relative to tumors growing in non-irradiated brain as evidenced by cohort differences in the ratios Glx/Lac (p < 0.01), Glx/Glc (p < 0.02), and Lac/Glc (p < 0.01).

Conclusions: A metabolic program skewed toward oxidative phosphorylation and away from glycolysis has been associated with immune dysfunction. This study documents such a skewed metabolic state in ICB refractory GL261 GBM growing in irradiated brain (tumors were not irradiated) compared to control brain.

查看原文本刊更多论文

代谢转移反映了抗pd - l1免疫治疗对GBM的免疫：一项氘MRS研究。

背景/目的：免疫检查点阻断（ICB）治疗在原发肿瘤标准治疗切除和放化疗后复发的胶质母细胞瘤（GBM）无效。在此，我们研究颅内放疗的延迟效应是否会改变肿瘤病变的代谢谱。方法：将Naïve（未辐照）GL261肿瘤细胞植入C57BL/6小鼠脑内。一个队列的大脑在植入前6周进行半半球照射，最终导致ICB难治性GBM。对照组的大脑未接受放射治疗。皮下输注[6,6- 2h2]葡萄糖（Glc）后，单体素氘代谢成像（DMI）监测Glc摄取和半重水（HOD）、2h2 -乳酸（Lac）和[2h2 -谷氨酸+ 2h2 -谷氨酰胺](Glx) 50/50混合物的产生。结果：GL261肿瘤在先前照射过的大脑中生长，相对于未照射过的大脑肿瘤，显示出较低的Warburg效应（有氧糖酵解，葡萄糖→乳酸）和较高的TCA循环活性（呼吸，氧化磷酸化），Glx/Lac比值的队列差异证明了这一点(p)。本研究记录了与对照脑相比，在辐照脑（肿瘤未辐照）中生长的ICB难治性GL261 GBM代谢状态的扭曲。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Molecular Imaging and Biology 医学-核医学

CiteScore

6.90

自引率

3.20%

发文量

审稿时长

3 months

期刊介绍： Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures. Some areas that are covered are: Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes. The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets. Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display. Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging. Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics. Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations. Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.