期刊
CELL METABOLISM
卷 33, 期 1, 页码 110-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2020.10.021
关键词
-
资金
- National Natural Science Foundation of China [81972779, 81902894, 81903036, 81622039, 81830054, 91859205, 81988101]
- Chinese National Key Project [2018ZX10723204006-003]
- Shanghai Municipal Commission of Education Project [201901070007E00065]
The study reveals that NAMPT enzyme drives PD-L1 expression in various tumors and governs tumor immune evasion through CD8(+) T cell regulation. NAD(+) metabolism maintains the activity and expression of Tet1, which plays a critical role in PD-L1 expression on tumors.
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 gamma (IFN gamma)-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 alpha-ketoglutarate (alpha-KG). IFN gamma-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 anti-body provides a promising therapeutic strategy for immunotherapy-resistant tumors.
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