Stress-Mediated Attenuation of Translation Undermines T Cell Tumor Control Article Swipe
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· 2022
· Open Access
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· DOI: https://doi.org/10.1101/2022.01.31.478547
· OA: W4210403005
Protein synthesis enables cell growth and survival, but the molecular mechanisms through which T cells suppress or maintain protein translation in the stress of solid tumors are unknown. Using mouse models and human tumors we demonstrate that protein translation in T cells is repressed by the solid tumor microenvironment (TME) due to activation of the unfolded protein response (UPR) via phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (p-eIF2α). Given that acute glucose deprivation in T cells exacerbated p-eIF2α, we show that metabolic reprogramming toward glycolytic independence allays the UPR and p-eIF2α, enabling sustained protein translation in T cells in TME stress. UPR mitigation was associated with enhanced degradation of proteins in antitumor T cells, as proteasome inhibition resulted in eIF2α phosphorylation, attenuation of translation, and loss of antitumor efficacy. In contrast, proteasome stimulation relieved translation inhibition, inducing robust T cell tumor control, offering a new therapeutic avenue to fuel the efficacy of tumor immunotherapy.
