Cell-Intrinsic Programs Partition Nutrients in Tumor Microenvironment

Tumor cells often rely on aerobic glycolysis, in which cells metabolize glucose to lactate in the presence of oxygen. Based on this characteristic, positron emission tomography (PET) using a radiolabeled glucose analogue has become a standard technique enabling the clinical detection and monitoring of tumor progression. Similar to cancer cells, immune cells in the tumor microenvironment (TME) also rely on glucose metabolism. To investigate whether immune cells and cancer cells may compete for access to nutrients, Reinfeld, Madden, and colleagues used PET to assess the uptake and metabolism of glucose across various cell subsets in the TME. Following in vivo administration of radioactive glucose analogue ¹⁸F-fluorodeoxyglucose (FDG) in multiple syngeneic murine tumor models, tumor-infiltrating CD45⁺ immune cells displayed a significantly greater uptake of FDG per cell than CD45⁻ cancer cells did. Fractionation of the TME into various immune subsets revealed that CD11b⁺ myeloid cells took up significantly more glucose than CD4⁺ or CD8⁺ effector T cells or CD45⁻ cancer cells. Specifically, monocytic myeloid-derived suppressor cells and tumor-associated macrophages were two myeloid populations that contributed to high glucose consumption, and both populations were enriched with transcripts associated with glucose-related pathways. When mice were treated with rapamycin to inhibit mammalian target of rapamycin complex 1 (mTORC1), known to promote anabolism and nutrient uptake, both immune cells and cancer cells exhibited decreased FDG uptake. To investigate whether glutamine, like glucose, was also partitioned between specific cell subsets in the TME, a glutamine radiotracer was administered to tumor-bearing mice and shown to preferentially partition into CD45⁻ cancer cells. When glutamine transport was inhibited pharmacologically, the uptake of glucose was increased in all TME cell subsets. Together, this work suggests that glutamine metabolism inhibits glucose metabolism and supports a model in which cell-intrinsic, mTORC1-driven programs dictate preferential glucose and glutamine metabolism in immune cells and cancer cells, respectively, in the TME.

Reinfeld BI, Madden MZ, Wolf MM, Chytil A, Bader JE, Patterson AR, et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 2021;593:282–8.

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