Immunotherapy using checkpoint blockers (antibodies) has been a major advance in recent years in the management of various types of solid cancers including lung cancer. One target of checkpoint blockers is programmed death ligand 1 (PD-L1) expressed by cancer cells, which engages programmed death 1 on T cells and Natural Killer (NK) cells resulting in suppression of their activation and cancer-killing function, respectively. Apart from antibodies, other clinically relevant agents that can inhibit PD-L1 are limited. PD-L1 protein stability depends on its glycosylation. Here we show that l-glutamine:d-fructose-6-phosphate amidotransferase 1 (GFAT1), a rate-limiting enzyme of the hexosamine biosynthesis pathway, which produces uridine diphosphate-N-acetyl-β-glucosamine, a precursor for glycosylation, is required for the stability of PD-L1 protein. Inhibition of GFAT1 activity markedly reduced interferon gamma (IFNγ)-induced PD-L1 levels in various lung cancer cell lines. GFAT1 inhibition suppressed glycosylation of PD-L1 and accelerated its proteasomal degradation. Importantly, inhibition of GFAT1 in IFNγ-treated cancer cells enhanced the activation of T cells and the cancer-killing activity of NK cells. These findings support using GFAT1 inhibitors to manipulate PD-L1 protein level that could augment the efficacy of immunotherapy for lung cancer.

中文翻译：

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抑制肺癌细胞中的 GFAT1 会破坏 PD-L1 蛋白的稳定性。

近年来，使用检查点阻滞剂（抗体）的免疫疗法在治疗包括肺癌在内的各种实体癌方面取得了重大进展。检查点阻滞剂的一个靶点是癌细胞表达的程序性死亡配体 1 (PD-L1)，它与 ​​T 细胞和自然杀伤 (NK) 细胞上的程序性死亡 1 结合，从而分别抑制它们的活化和杀癌功能。除抗体外，其他可抑制 PD-L1 的临床相关药物也很有限。PD-L1 蛋白的稳定性取决于其糖基化。在这里，我们展示了 l-谷氨酰胺：d-果糖-6-磷酸氨基转移酶 1 (GFAT1)，一种己糖胺生物合成途径的限速酶，可产生尿苷二磷酸-N-乙酰基-β-葡萄糖胺，糖基化的前体，是 PD-L1 蛋白稳定性所必需的。GFAT1 活性的抑制显着降低了各种肺癌细胞系中干扰素 γ (IFNγ) 诱导的 PD-L1 水平。GFAT1 抑制抑制 PD-L1 的糖基化并加速其蛋白酶体降解。重要的是，在 IFNγ 处理的癌细胞中抑制 GFAT1 可增强 T 细胞的活化和 NK 细胞的杀癌活性。这些发现支持使用 GFAT1 抑制剂来控制 PD-L1 蛋白水平，从而增强肺癌免疫疗法的疗效。在 IFNγ 处理的癌细胞中抑制 GFAT1 可增强 T 细胞的活化和 NK 细胞的杀癌活性。这些发现支持使用 GFAT1 抑制剂来控制 PD-L1 蛋白水平，从而增强肺癌免疫疗法的疗效。在 IFNγ 处理的癌细胞中抑制 GFAT1 可增强 T 细胞的活化和 NK 细胞的杀癌活性。这些发现支持使用 GFAT1 抑制剂来控制 PD-L1 蛋白水平，从而增强肺癌免疫疗法的疗效。