Stress-Mediated Attenuation of Translation Undermines T-cell Activity in Cancer.
Stress-Mediated Attenuation of Translation Undermines T-cell Activity in Cancer.
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DOI：
10.1158/0008-5472.can-22-1744
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发表时间：
2022-12-02
期刊：
影响因子：
11.2
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中科院分区：
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蛋白质合成支持强大的免疫反应。肿瘤微环境（TME）中的营养竞争和整体细胞应激因子可能会影响T细胞中的蛋白质翻译和抗肿瘤免疫。使用人类和小鼠肿瘤，我们在这里证明了T细胞中的蛋白质翻译在实体瘤中受到抑制。TME中T细胞的葡萄糖可用性降低导致未折叠蛋白反应（UPR）元件eIF 2 α的激活。遗传小鼠模型显示，活化的p-eIF 2 α介导的翻译衰减破坏了T细胞抑制肿瘤生长的能力。重编程T细胞代谢能够减轻TME中的p-eIF 2 α积累和翻译衰减，从而允许持续的蛋白质翻译。代谢和药理学方法表明，蛋白酶体活性减轻了p-eIF 2 α的诱导，以支持最佳的抗肿瘤T细胞功能，防止翻译衰减，并使实体瘤中的细胞因子合成延长。总之，这些数据确定了一种新的治疗途径，以提高肿瘤免疫治疗的疗效。
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. Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2α undermines the ability of T cells to suppress tumor growth. Reprogramming 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.