NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion

• Published in: Cell metabolism Vol. 33; no. 1; pp. 110 - 127.e5
• Main Authors: Lv, Hongwei, Lv, Guishuai, Chen, Cian, Zong, Qianni, Jiang, Guoqing, Ye, Dan, Cui, Xiuliang, He, Yufei, Xiang, Wei, Han, Qin, Tang, Liang, Yang, Wen, Wang, Hongyang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.01.2021
• Subjects: cancer immune evasion; cancer immunotherapy; epigenetics; immune checkpoint blockade; interferon γ; NAD+ metabolism; NAMPT; PD-L1; Tet1; cancer immune evasion; NAD+ metabolism; NAMPT; interferon γ; cancer immunotherapy; PD-L1; Tet1; epigenetics; immune checkpoint blockade; NAD(+) metabolism
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2020.10.021

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. [Display omitted] •NAD+ metabolism drives tumor immune evasion in a CD8+ T cell-dependent manner•NAD+/α-KG-mediated Tet1 synergizes with IFNγ signaling to regulate PD-L1 expression•An activated NAMPT-TET1-p-STAT1-IRF1-PD-L1 axis in human cancer predicts poor outcome•NAD+ replenishment sensitizes anti-PD-(L)1 therapy-resistant tumors to immunotherapy NAD+ metabolism is implicated in aging and cancer. However, its role in tumor immunity remains unclear. Here, Lv et al. find that nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme of the NAD+ biogenesis, drives inducible PD-L1 immune checkpoint expression in multiple tumors and governs tumor immune evasion. 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, providing a promising therapeutic strategy for immunotherapy-resistant tumors.