Immu-37. Metabolic Reprogramming of the Glioma Microenvironment Inhibits Tumor Immunosuppression
Year: 2017
Type: conference-abstract
Abstract: Anti-tumor immunity in murine models of glioblastoma is potently suppressed by regulatory T-cell (Treg) accumulation within the tumor. Recent studies have highlighted that both glioma and immunosuppressive cellular subsets utilize fatty acid metabolism for survival. Inhibition of fatty acid oxidation (FAO) prolongs survival in glioma bearing mice, however, the immunity of tumor microenvironment (TME) upon inhibition of this pathway is not known. In this study we looked at the immunological effects of etomoxir, an inhibitor of mitochondrial import of fatty acids (FA) on an intracranial model of glioma. We tested both intracranial and systemic administration of this inhibitor to understand effects on systemic immunity as well as specifically within the TME. Glioma bearing mice had significantly increased free fatty acids within the interstitial fluid of the tumor, suggesting this may be an abundant energy source within this environment. We measured the effect of etomoxir on the GL261 murine tumor line, and found minimal effects on glioma cultures, with cytostatic effects occurring only at very high concentrations. Through the use of a novel nanoparticle-FA sensor, we observed that Tregs uptake significantly more FA compared to effector T-cells in tumor bearing mice and may be the target of FAO inhibition. We demonstrate a significant increase in survival with intracranial etomoxir treatment (p<0.01, **), which does not occur in immunodeficient animals. Both intracranial and systemic Etomoxir treatment caused a significant decrease in total number of Tregs within the glioma tissue, with a concomitant increase in CD8 T-cell functionality. Our data suggests that that FA metabolism contributes to the immunosuppressive TME, and may be a metabolic target to enhance immunotherapy against glioma.
Source: Neuro-Oncology
Institution: Northwestern University
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2767997135