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NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion
- Source :
- Cell Metabolism. 33:110-127.e5
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
biology
Physiology
Chemistry
medicine.medical_treatment
Nicotinamide phosphoribosyltransferase
Cell Biology
Immune checkpoint
Cell biology
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
0302 clinical medicine
Immune system
IRF1
Cancer immunotherapy
PD-L1
medicine
biology.protein
NAD+ kinase
Antibody
Molecular Biology
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15504131
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- Cell Metabolism
- Accession number :
- edsair.doi...........f3d2b6a84324bf995cfe043ece910b75