A glutamine 'tug-of-war': targets to manipulate glutamine metabolism for cancer immunotherapy

Abstract

Within the tumour microenvironment (TME), there is a cellular 'tug-of-war' for glutamine, the most abundant amino acid in the body. This competition is most evident when considering the balance between a successful anti-tumour immune response and the uncontrolled growth of tumour cells that are addicted to glutamine. The differential effects of manipulating glutamine abundance in individual cell types is an area of intense research and debate. Here, we discuss some of the current strategies in development altering local glutamine availability focusing on inhibition of enzymes involved in the utilisation of glutamine and its uptake by cells in the TME. Further studies are urgently needed to complete our understanding of glutamine metabolism, to provide critical insights into the pathways that represent promising targets and for the development of novel therapeutic strategies for the treatment of advanced or drug resistant cancers.

Keywords: T cells; cancer immunotherapy; glutamine.

Figure 1.

Glutamine is taken up into cells via glutamine transporters including SLC1A5 (ASCT2), SLC38A1 (SNAT1) and SLC38A2 (SNAT2). Inside the cell glutamine can serve as a substrate for various pathways, such as the synthesis of nucleotides. Glutamine is converted by cytosolic and mitochondrial glutaminases to glutamate a substrate for conversion by aminotransferase or glutamate dehydrogenase to 2-oxalogluterate, which enter the TCA cycle, for the generation of ATP, or the production of acetyl-CoA and NADPH, both of which can fuel lipid metabolism or generate pyruvate. Glutamate further contributes as a precursor to the generation of the anti-oxidant glutathione and amino acids proline, alanine and aspartate. Glutamate can be exported from the cell to allow uptake of cystine, through the antiporter SLC7A11 (xCT). Other essential amino acids, including methionine, leucine and tryptophan are brought into the cell through the anti-porter SLC7A5, which uses glutamine as the exchange currency.