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Tumour immunology

An exhausting metabolic competition

Nature Reviews Cancer volume 15, page 573 (2015)Cite this article

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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.

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References

  1. Chang, C.-H., Qiu, J. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015)

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  2. Ho, P. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015)

    Article  CAS  Google Scholar 

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Authors
  1. Sarah Seton-Rogers
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Seton-Rogers, S. An exhausting metabolic competition. Nat Rev Cancer 15, 573 (2015). https://doi.org/10.1038/nrc4014

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