肿瘤微环境
综合应力响应
翻译(生物学)
蛋白质生物合成
蛋白酶体
真核翻译
免疫系统
生物
癌症研究
免疫疗法
癌症
细胞生物学
免疫学
信使核糖核酸
生物化学
遗传学
基因
作者
Brian Riesenberg,Elizabeth G. Hunt,Megan D. Tennant,Katie E. Hurst,Alex M. Andrews,Lee R. Leddy,David M. Neskey,Elizabeth G. Hill,Guillermo O. Rangel Rivera,Chrystal M. Paulos,Peng Gao,Jessica E. Thaxton
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2022-09-20
卷期号:82 (23): 4386-4399
被引量:3
标识
DOI:10.1158/0008-5472.can-22-1744
摘要
Abstract Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvironment (TME) may impact protein translation in T cells and antitumor immunity. Using human and mouse tumors, we demonstrated here that protein translation in T cells is repressed in solid tumors. Reduced glucose availability to T cells in the TME led to activation of the unfolded protein response (UPR) element eIF2α (eukaryotic translation initiation factor 2 alpha). Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2α undermines the ability of T cells to suppress tumor growth. Reprograming T-cell metabolism was able to alleviate p-eIF2α accumulation and translational attenuation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that proteasome activity mitigates induction of p-eIF2α to support optimal antitumor T-cell function, protecting from translation attenuation and enabling prolonged cytokine synthesis in solid tumors. Together, these data identify a new therapeutic avenue to fuel the efficacy of tumor immunotherapy. Significance: Proteasome function is a necessary cellular component for endowing T cells with tumor killing capacity by mitigating translation attenuation resulting from the unfolded protein response induced by stress in the tumor microenvironment.
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