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Background/Objectives <p>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.</p> Methods <p>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-<sup>2</sup>H<sub>2</sub>] glucose (Glc), single voxel deuterium metabolic imaging (DMI) monitored Glc uptake and the production of semi-heavy water (HOD), <sup>2</sup>H<sub>2</sub>-lactate (Lac) and the 50/50 mix of [<sup>2</sup>H<sub>2</sub>-glutamate + <sup>2</sup>H<sub>2</sub>-glutamine] (Glx).</p> Results <p>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 &lt; 0.01), Glx/Glc (p &lt; 0.02), and Lac/Glc (p &lt; 0.01).</p> Conclusions <p>A metabolic program skewed&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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

摘要

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.