Nicotinamide phosphoribosyltransferase modulates PD-L1 in bladder cancer and enhances immunotherapeutic sensitivity

Kuan Chou Chen, Trayee Dhar, Chang Rong Chen, Eugene Chang Yu Chen, Chiung Chi Peng

Research output: Contribution to journalArticlepeer-review

Abstract

Bladder cancer (BLCA) is one of the most prevalent malignancies worldwide with a high mortality rate and poor response to immunotherapy in patients expressing lower programmed death ligand 1 (PD-L1) levels. Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme responsible for the biosynthesis of nicotinamide adenine dinucleotide (NAD+) from nicotinamide was reported to be overexpressed in various cancers; however, the role of NAMPT in BLCA is obscure. Immunohistochemistry of tissue microarrays, a real-time polymerase chain reaction, Western blotting, proliferation assay, NAD+ quantification, transwell-migration assay, and colony-formation assay were performed to measure NAMPT and PD-L1 expression levels in patients and the effect of NAMPT inhibition on T24 cells. Our study revealed that NAMPT expression was upregulated in BLCA patients with different grades and associated with poor T-cell infiltration. Notably, FK866-mediated NAMPT inhibition decreased cell viability by depleting NAD+, and reducing the migration ability and colony-formation ability of T24 cells. Interestingly, NAMPT negatively regulated PD-L1 under an interferon (IFN)-γ-mediated microenvironment. However, exogenous NAMPT activator has no effect on PD-L1. NAD+ supplementation also only increased PD-L1 in the absence of IFN-γ. Conclusively, NAMPT is crucial for BLCA tumorigenic properties, and it regulates expression of the PD-L1 immune checkpoint protein. NAMPT could be considered a target for modulating sensitivity to immunotherapy.

Original languageEnglish
Article number167106
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1870
Issue number4
DOIs
Publication statusPublished - Apr 2024

Keywords

  • Bladder cancer (BLCA)
  • NAMPT (nicotinamide phosphoribosyltransferase)
  • PD-L1 (programmed death ligand 1)
  • Tumor microenvironment (TME)

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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