Cell Programmed Nutrient Partitioning in the Tumor Microenvironment

Abstract

The tumor microenvironment (TME) includes transformed cancer and infiltrating immune cells. Cancer cells can consume large quantities of glucose through Warburg metabolism that can be visualized with positron emission tomography (PET). While infiltrating immune cells also rely on glucose, disruptions to metabolism can contribute to tumor immunological evasion. How immune cell metabolism is programmed or restrained by competition with cancer cells for nutrients, remains uncertain. Here we used PET tracers to measure the accessibility of glucose and glutamine to cell subsets in the TME. Surprisingly, myeloid cells including macrophages were the greatest consumers of intra-tumoral glucose, followed by T cells and cancer cells. Cancer cells, in contrast, had the highest glutamine uptake. This distinct nutrient partitioning was programmed through selective mTORC1 signaling and glucose or glutamine-related gene expression. Inhibition of glutamine uptake enhanced glucose uptake across tumor resident cell types and shifted macrophage phenotype, demonstrating glucose is not limiting in the TME. Thus, cancer cells are not the only cells in tumors which exhibit high glucose uptake in vivo and instead preferentially utilize glutamine over other cell types. We observe that intrinsic cellular programs can play a major role in the use of some nutrients. Together, these data argue cell selective partitioning of glucose and glutamine can be exploited to develop therapies and imaging strategies to alter the metabolic programs of specific cell populations in the TME.

Comprehensive analysis of m6A/m5C/m1A-related gene expression, immune infiltration, and sensitivity of antineoplastic drugs in glioma

“…There were significant differences in the scores of 17 immune function gene sets between the two clusters. A recent study (34) has reported that it is not the cancer cells that consume a considerable amount of glucose. The researchers used 18F-FDG-PET to detect glucose consumption in mouse tumor models to quantify glucose intake by different cell populations in the tumor microenvironment.…”

Characterization of the Immune Cell Infiltration Profile in Pancreatic Carcinoma to Aid in Immunotherapy

“…Previous studies have suggested that, in TME, competition for nutrients between cancer cells and T cells contributes to immunosuppression ( 45 , 46 ). Moreover, a recent study evaluated metabolic features of tumor cell types in vivo and revealed that individual cell populations had distinct programs of nutrient uptake that might serve an important role in the development of future cancer therapies by altering TME ( 47 ). In addition, we, also, observed markedly elevated expression of cell cycle- and DNA repair- (mismatch repair and nucleotide excision repair) related genes in the high ICI score group.…”

Distinct bioenergetic features of human invariant natural killer T (iNKT) cells enable retained functions in nutrient-deprived states

“…The TME imposes metabolic challenges to the functions of T cells and other immune cells that directly impact antitumor immunity and tumor progression. As cancer and myeloid cells employ aerobic glycolysis to support biosynthetic requirements for proliferation via the Warburg effect, they rapidly uptake glucose, glutamine, and amino acids, depleting the TME of these nutrients (DeBerardinis and Chandel, 2016; Ghoshdastider et al, 2021; Pavlova and Thompson, 2016; Reinfeld et al, 2021); furthermore, the poor vasculature creates regions of hypoxia within the TME. As such, the hypoxic, acidic, nutrient-deplete TME impairs the ability of T CONV to sustain their functional activity.…”