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

TL;DR

This study shows that brain tumors in previously irradiated areas have a different metabolism linked to poor response to immunotherapy.

Contribution

The study links metabolic changes in irradiated brains to immunotherapy resistance in glioblastoma using deuterium MRS.

Findings

Tumors in irradiated brains showed reduced glycolysis and increased TCA cycle activity.

Metabolic shifts correlated with immune dysfunction and resistance to anti-PD-L1 therapy.

Abstract

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.

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).

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).

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.

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