An exhausting metabolic competition

Credit: adamelder / Stockimo / Alamy Stock Photo

Several mechanisms might explain why tumour-infiltrating lymphocytes (TILs) do not eradicate some tumours. Two studies have shown that reduction of glucose levels in the tumour microenvironment by highly glycolytic tumour cells reduces the ability of TILs to trigger an antitumour immune response.

Chang, Qiu et al. used an established model of regressing (R) and progressing (P) sarcomas. R tumour cells express a key rejection antigen, whereas P tumour cells do not. Tumour rejection in vivo also requires interferon-γ (IFNγ) production by T cells, and IFNγ production by T cells co-cultured with R or P tumour cells correlated with the amount of glucose in the media. When P tumours were grown in immunocompetent mice, they consumed more glucose, and the TILs were glucose-restricted and had reduced effector functions compared with TILs in R tumours. R tumour cells that were selected for high levels of glycolysis gained a progressor phenotype in vivo, independent of effects on cell proliferation or survival, suggesting that reduced glucose availability can restrict antitumour TIL functions.

Interestingly, TILs from P tumour-bearing mice treated with immune checkpoint inhibitors had increased rates of glycolysis and produced higher levels of IFNγ, indicating that checkpoint inhibitors might increase TIL metabolism. The authors also considered the possibility that the immune checkpoint protein PD1 ligand 1 (PDL1), which is expressed by tumour cells, might have functions beyond inhibiting T cells. Indeed, antagonizing PDL1 in P tumour cells reduced their glycolytic activity and increased concentrations of glucose in the tumour microenvironment. Therefore, increasing available glucose for T cells by reducing tumour cell glycolysis might underlie, in part, the therapeutic benefit of PDL1 inhibition.

Ho et al. observed that CD4⁺ T cells in melanomas in mice did not efficiently take up glucose and had suppressed effector functions (such as IFNγ and CD40 ligand (CD40L) production), indicating that tumour cells might restrict glucose availability for these TILs. Melanoma cells overexpressing the glycolytic enzyme hexokinase 2 (HK2 cells) had higher rates of glycolysis than control cells and more efficiently suppressed glucose uptake of co-cultured CD4⁺ T cells and of CD4⁺ T cells isolated from tumours. Furthermore, when HK2 cells were engrafted in immunocompetent mice, IFNγ and CD40L production by CD4⁺ TILs was reduced.

tumours can suppress antitumour T cell responses through glucose deprivation

Looking more closely at signalling pathways in glucose-deprived CD4⁺ T cells, the authors found that T cell receptor-induced Ca²⁺ flux and downstream nuclear translocation of nuclear factor of activated T cells 1 (NFAT1) were repressed. Under glucose deprivation, T cells had increased activity of the endoplasmic reticulum Ca²⁺ channel SERCA, which reduced cytosolic Ca²⁺ levels; inhibition of SERCA restored NFAT1 nuclear translocation and production of IFNγ and CD40L. Analyses of glycolytic metabolites in T cells indicated that phosphoenolpyruvate (PEP) is a crucial regulator of T cell function, SERCA and Ca²⁺–NFAT1 signalling. To assess the role of this pathway on tumours in vivo, the authors overexpressed PEP carboxykinase 1 (PCK1), which induces PEP production, in CD4⁺ T cells that were then adoptively transferred into mice bearing melanomas. PCK1-expressing cells were associated with reduced tumour growth compared with control T cells and significantly increased the survival of the mice. This suggests that reprogramming T cells to increase PEP levels in a glucose-deprived environment can increase their antitumour functions.

These studies support the hypothesis that tumours can suppress antitumour T cell responses through glucose deprivation. Restoring glucose in the tumour microenvironment or otherwise reprogramming T cell metabolism might improve cancer immunotherapy.