NAD+ supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells

Abstract

Highlights d Levels of NAD+ and NAMPT are decreased in TILs compared to those of other T cells d Tubby is a transcriptional factor for NAMPT in T cells d NAMPT-mediated NAD+ production is essential for T cell activation by generating ATP d NAD+ supplementation enhances the tumor-killing function of T cells

Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion

“…Given the role of NAD + in T cell differentiation ( Wang et al., 2021 ), we asked whether NADase CD38 deficiency impacted the CD8 + T cell development/homeostasis and function. Analyses of T cell development in the thymus have shown that CD38 knockout did not disturb the development of T cells including the maturation of CD4 + and CD8 + single-positive population ( Figures 2 A and 2B).…”

“…Recently, Wang et al. reported that the disturbance of NAD + metabolism impacted the activation and tumor-killing function of CD8 + T cells in vivo ( Wang et al., 2021 ). As one of the well-known NAD + consuming enzymes, CD38 was positively correlated with the dysfunctionality of CD8 + T cells in the tumor ( Philip et al., 2017 ; Verma et al., 2019 ).…”

“…Recently, Wang et al. reported that the downregulation of NAMPT—the rate-limiting enzyme of NAD + salvage pathway—could decrease NAD + levels in tumor-infiltrated T cells ( Wang et al., 2021 ). Thus, it remains to be addressed whether simultaneous targeting of several NADase is able to relieve CD8 + T cell exhaustion state.…”

Erythroid Differentiation Regulator 1 Strengthens TCR Signaling by Enhancing PLCγ1 Signal Transduction Pathway

“…In addition, there exists a report describing that Erdr1 expression is increased in brains from TUB gene-mutated mice [ 36 ]. It is interesting because Tubby protein, a membrane-bound protein, acts as a transcription factor and enhances T cell activation in a PLCγ dependent manner [ 37 ]. From these studies, it is conjectured that components of the cell membrane may be involved in the TCR signal modulating the function of Erdr1.…”

Effect of CRISPR/Cas9-Edited PD-1/PD-L1 on Tumor Immunity and Immunotherapy

“…Inhibition of Fut8 can reduce PD-1 expression on the cell surface, enhance T cell activation, and eradicate tumors more effectively ( 84 ). Using genome-wide CRISPR and metabolic inhibitor screening, Wang determined that nicotinamide phosphoribotransferase (NAMPT) is required for T cell activation and demonstrated that NAD+ supplementation significantly enhances anti-PD-1 immunotherapy in a mouse solid tumor model ( 85 ). This demonstrates the feasibility of CRISPR/Cas9 screening technology in discovering PD-1-related regulatory factors and provides a more comprehensive strategy for in-depth exploration of the PD-1 regulatory mechanism.…”