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NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion
Cell Metabolism ( IF 29.0 ) Pub Date : 2020-11-09 , DOI: 10.1016/j.cmet.2020.10.021
Hongwei Lv 1 , Guishuai Lv 2 , Cian Chen 3 , Qianni Zong 3 , Guoqing Jiang 4 , Dan Ye 5 , Xiuliang Cui 3 , Yufei He 3 , Wei Xiang 6 , Qin Han 3 , Liang Tang 3 , Wen Yang 3 , Hongyang Wang 7
Affiliation  

NAD+ metabolism is implicated in aging and cancer. However, its role in immune checkpoint regulation and immune evasion remains unclear. Here, we find nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ biogenesis, drives interferon γ (IFNγ)-induced PD-L1 expression in multiple types of tumors and governs tumor immune evasion in a CD8+ T cell-dependent manner. Mechanistically, NAD+ metabolism maintains activity and expression of methylcytosine dioxygenase Tet1 via α-ketoglutarate (α-KG). IFNγ-activated Stat1 facilitates Tet1 binding to Irf1 to regulate Irf1 demethylation, leading to downstream PD-L1 expression on tumors. Importantly, high NAMPT-expressing tumors are more sensitive to anti-PD-L1 treatment and NAD+ augmentation enhances the efficacy of anti-PD-L1 antibody in immunotherapy-resistant tumors. Collectively, these data delineate an NAD+ metabolism-dependent epigenetic mechanism contributing to tumor immune evasion, and NAD+ replenishment combined with PD-(L)1 antibody provides a promising therapeutic strategy for immunotherapy-resistant tumors.



中文翻译:

NAD+ 代谢维持可诱导的 PD-L1 表达以驱动肿瘤免疫逃避

NAD +代谢与衰老和癌症有关。然而,其在免疫检查点调节和免疫逃避中的作用仍不清楚。在这里,我们发现烟酰胺磷酸核糖基转移酶 (NAMPT),NAD +生物发生的限速酶,在多种类型的肿瘤中驱动干扰素 γ (IFNγ) 诱导的 PD-L1 表达,并控制 CD8 + T 细胞中的肿瘤免疫逃避。依赖方式。从机制上讲,NAD +代谢通过 α-酮戊二酸 (α-KG) 维持甲基胞嘧啶双加氧酶 Tet1 的活性和表达。IFNγ 激活的 Stat1 促进 Tet1 与 Irf1 结合以调节 Irf1 去甲基化,从而导致肿瘤上下游的 PD-L1 表达。重要的是,高表达 NAMPT 的肿瘤对抗 PD-L1 治疗更敏感,NAD +增强增强了抗 PD-L1 抗体在免疫治疗耐药肿瘤中的疗效。总的来说,这些数据描绘了 NAD +代谢依赖性表观遗传机制,有助于肿瘤免疫逃避,NAD +补充与 PD-(L)1 抗体相结合为免疫治疗耐药肿瘤提供了一种有前景的治疗策略。

更新日期:2021-01-05
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