Altered Metabolism in Glioblastoma: Myeloid-Derived Suppressor Cell (MDSC) Fitness and Tumor-Infiltrating Lymphocyte (TIL) Dysfunction

Abstract

The metabolism of glioblastoma (GBM), the most aggressive and lethal primary brain tumor, is flexible and adaptable to different adverse conditions, such as nutrient deprivation. Beyond glycolysis, altered lipid metabolism is implicated in GBM progression. Indeed, metabolic subtypes were recently identified based on divergent glucose and lipid metabolism. GBM is also characterized by an immunosuppressive microenvironment in which myeloid-derived suppressor cells (MDSCs) are a powerful ally of tumor cells. Increasing evidence supports the interconnection between GBM and MDSC metabolic pathways. GBM cells exert a crucial contribution to MDSC recruitment and maturation within the tumor microenvironment, where the needs of tumor-infiltrating lymphocytes (TILs) with antitumor function are completely neglected. In this review, we will discuss the unique or alternative source of energy exploited by GBM and MDSCs, exploring how deprivation of specific nutrients and accumulation of toxic byproducts can induce T-cell dysfunction. Understanding the metabolic programs of these cell components and how they impact fitness or dysfunction will be useful to improve treatment modalities, including immunotherapeutic strategies.

Keywords: glioblastoma; metabolism; myeloid derived suppressor cells (MDSCs), tumor infiltrating lymphocytes (TILs).

Figure 1

Metabolic symbiosis between GBM and MDSCs and therapeutic potential of T cell metabolic targeting. The figure shows as tumor cells and MDSCs, in a hypermetabolic state, interact to promote an immunosuppressive environment, and some mechanisms of modulation to improve the metabolic performance of T cells. Gln: Glutamine; Arg: Arginine; Trp: Tryptophan; TME: Tumor microenvironment; FA: Fatty acids; TIL: Tumor infiltrating lymphocytes; CAR: Chimeric antigen receptor. Figure adapted from images created with BioRender.com.