International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, China; Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai 200438, China.
International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer, Second Military Medical University, Shanghai 201805, China; Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai 200438, China.
Cell Metab. 2021 Jan 5;33(1):110-127.e5. doi: 10.1016/j.cmet.2020.10.021. Epub 2020 Nov 9.
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.
NAD 代谢与衰老和癌症有关。然而，其在免疫检查点调控和免疫逃逸中的作用尚不清楚。在这里，我们发现烟酰胺磷酸核糖转移酶（NAMPT）是 NAD 生物合成的限速酶，它驱动多种类型肿瘤中干扰素 γ（IFNγ）诱导的 PD-L1 表达，并以 CD8 T 细胞依赖的方式控制肿瘤免疫逃逸。在机制上，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，调节 Irf1 去甲基化，从而导致肿瘤中 PD-L1 的下游表达。重要的是，高表达 NAMPT 的肿瘤对抗 PD-L1 治疗更敏感，NAD 补充增强了抗 PD-L1 抗体在免疫治疗耐药肿瘤中的疗效。总之，这些数据描绘了一种依赖 NAD 代谢的表观遗传机制，该机制有助于肿瘤免疫逃逸，NAD 补充联合 PD-(L)1 抗体为免疫治疗耐药肿瘤提供了一种有前途的治疗策略。
