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NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion
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...
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Published in: | Cell metabolism 2021-01, Vol.33 (1), p.110-127.e5 |
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Main Authors: | , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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.
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•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. |
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ISSN: | 1550-4131 1932-7420 |
DOI: | 10.1016/j.cmet.2020.10.021 |