Abstract
Current immunotherapies yield remarkable clinical outcomes by boosting the power of host immunity in cancer cell elimination and viral clearance. However, after prolonged antigen exposure, CD8+ T cells differentiate into a special differentiation state known as T-cell exhaustion, which poses one of the major hurdles to antiviral and antitumor immunity during chronic viral infection and tumour development. Growing evidence indicates that exhausted T cells undergo metabolic insufficiency with altered signalling cascades and epigenetic landscapes, which dampen effector immunity and cause poor responsiveness to immune-checkpoint-blockade therapies. How metabolic stress affects T-cell exhaustion remains unclear; therefore, in this Review, we summarize current knowledge of how T-cell exhaustion occurs, and discuss how metabolic insufficiency and prolonged stress responses may affect signalling cascades and epigenetic reprogramming, thus locking T cells into an exhausted state via specialized differentiation programming.
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Acknowledgements
P.-C.H. was supported in part by a European Research Council Staring Grant (802773-MitoGuide), the Swiss National Science Foundation (31003A_182470), the Swiss Institute for Experimental Cancer Research (ISREC 26075483), the Swiss Cancer League (KFS-3949-08-2016), a Swiss Bridge Award, a Cancer Research Institute–CLIP Investigator award and an EMBO Young Investigator award.
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F.F., A.J., P.R., Y.-R.Y. and P.-C.H. wrote manuscript. A.J. and Y.-R.Y. produced the figures and table.
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P.-C.H. is serving as a scientific advisory board member for Elixiron Immunotherapeutics and Acepodia. P.-C.H. receives research grants from Roche and has received honoraria from Pfizer and Chugai. P.R. also receives research grants from Roche. The other authors have no conflict of interest.
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Franco, F., Jaccard, A., Romero, P. et al. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab 2, 1001–1012 (2020). https://doi.org/10.1038/s42255-020-00280-9
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DOI: https://doi.org/10.1038/s42255-020-00280-9
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