The role of tumor microenvironment (TME)–associated inadequate protein modification and trafficking due to insufficiency in Golgi function, leading to Golgi stress, in the regulation of T cell function is largely unknown. Here, we show that disruption of Golgi architecture under TME stress, identified by the decreased expression of GM130, was reverted upon treatment with hydrogen sulfide (H 2 S) donor GYY4137 or overexpressing cystathionine β-synthase (CBS), an enzyme involved in the biosynthesis of endogenous H 2 S, which also promoted stemness, antioxidant capacity, and increased protein translation, mediated in part by endoplasmic reticulum–Golgi shuttling of Peroxiredoxin-4. In in vivo models of melanoma and lymphoma, antitumor T cells conditioned ex vivo with exogenous H 2 S or overexpressing CBS demonstrated superior tumor control upon adoptive transfer. Further, T cells with high Golgi content exhibited unique metabolic and glycation signatures with enhanced antitumor capacity. These data suggest that strategies to mitigate Golgi network stress or using Golgi hi tumor-reactive T cells can improve tumor control upon adoptive transfer.

中文翻译：

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H 2 S-Prdx4 轴减轻高尔基体应激以增强肿瘤反应性 T 细胞免疫治疗反应


由于高尔基体功能不足导致高尔基体应激，肿瘤微环境 （TME） 相关的蛋白质修饰和运输不足在 T 细胞功能的调节中的作用在很大程度上是未知的。在这里，我们表明，在 TME 胁迫下，由 GM130 表达降低所鉴定的高尔基体结构破坏在用硫化氢 （H 2 S） 供体 GYY4137 处理或过表达胱硫醚 β-合酶 （CBS） 后恢复，这是一种参与内源性 H 2 S 生物合成的酶，它还促进了干性、抗氧化能力和增加的蛋白质翻译， 部分由过氧化物还原蛋白-4 的内质网-高尔基体穿梭介导。在黑色素瘤和淋巴瘤的体内模型中，体外用外源性 H 2 S 或过表达 CBS 条件的抗肿瘤 T 细胞在过继转移时表现出优异的肿瘤控制。此外，高尔基体含量高的 T 细胞表现出独特的代谢和糖基化特征，具有增强的抗肿瘤能力。这些数据表明，减轻高尔基体网络压力或使用高尔基体高肿瘤反应性 T 细胞的策略可以改善过继转移时的肿瘤控制。