Editors' ChoiceCancer Immunotherapy

Exploiting human Tregs’ sweet tooth to improve cancer immunotherapy

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Science Translational Medicine  07 Nov 2018:
Vol. 10, Issue 466, eaav6058
DOI: 10.1126/scitranslmed.aav6058


TLR8 activation enhances cancer immunotherapy by reprograming of glucose metabolism in regulatory T cells.

The tumor microenvironment often favors differentiation and recruitment of regulatory T cells (Tregs), which suppress antitumor effector T cell function and constitute a major obstacle for immunotherapy. Cellular metabolism instructs T cell differentiation and function; Tregs in mice are widely believed to mainly rely on oxidative phosphorylation, whereas effector T cells require glycolysis for proper function. However, it remains contentious whether this dichotomy applies to human T cells. Furthermore, there is ongoing investigation of immune cell metabolic targets for treatment of immune-related diseases, including cancer.

Li and colleagues carefully examined major steps of glucose metabolism in different human T cell subsets. Their data showed that, unlike mouse Tregs, human Tregs exhibit enhanced glucose uptake and glycolysis compared with effector T cells. Toll-like receptor 8 (TLR8) is a nucleic acid–sensing receptor primarily expressed on human Tregs and dendritic cells but not on effector T cells. Due to several mutations, TLR8 is not functional on mouse cells. TLR8 stimulation reduced expression of glucose transporters and glycolytic processes of human Tregs and hence diminished their suppressive activity. Mechanistically, TLR8 activation suppressed the mechanistic target of rapamycin complex 1 (mTORC1)–hypoxia-inducible factor 1 (HIF1) signaling pathway that promotes glucose metabolism. Thus, human Tregs require enhanced glucose metabolism to maintain their function. Importantly, TLR8 activation did not modulate effector T cells, likely due to its low expression on effector T cells. To test if targeting Treg glucose metabolism could improve cancer immunotherapy, the authors established a humanized mouse model of melanoma immunotherapy by inoculating human melanoma cells and transferring tumor-specific human CD8+ T cells into immunodeficient mice. Cotransfer of human Tregs reversed the beneficial effects of the CD8+ T cells; transfer of human Tregs treated with TLR8 agonist or a glycolysis inhibitor led to further reduced tumor burden.

This study identifies glucose metabolism in human Tregs as a promising target to improve cancer immunotherapy. Moreover, it illustrates some significant differences in terms of metabolic requirement between mouse and human Tregs, highlighting the importance of human immunology research. It should be noted that the melanoma model used in the study was reductionist because the entire immune system was constituted with transferred CD8+ T cells and Tregs. Thus, more preclinical and clinical research is needed to confirm the veracity of this approach for cancer immunotherapy.

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