G6PD functions as a metabolic checkpoint to regulate granzyme B expression in tumor-specific cytotoxic T lymphocytes

Abstract

BackgroundGranzyme B is a key effector of cytotoxic T lymphocytes (CTLs), and its expression level positively correlates with the response of patients with mesothelioma to immune checkpoint inhibitor immunotherapy. Whether metabolic pathways regulate Gzmb expression in CTLs is incompletely understood.MethodsA tumor-specific CTL and tumor coculture model and a tumor-bearing mouse model were used to determine the role of glucose-6-phosphate dehydrogenase (G6PD) in CTL function and tumor immune evasion. A link between granzyme B expression and patient survival was analyzed in human patients with epithelioid mesothelioma.ResultsMesothelioma cells alone are sufficient to activate tumor-specific CTLs and to enhance aerobic glycolysis to induce a PD-1hi Gzmblo CTL phenotype. However, inhibition of lactate dehydrogenase A, the key enzyme of the aerobic glycolysis pathway, has no significant effect on tumor-induced CTL activation. Tumor cells induce H3K9me3 deposition at the promoter of G6pd, the gene that encodes the rate-limiting enzyme G6PD in the pentose phosphate pathway, to downregulate G6pd expression in tumor-specific CTLs. G6PD activation increases acetyl-coenzyme A (CoA) production to increase H3K9ac deposition at the Gzmb promoter and to increase Gzmb expression in tumor-specific CTLs converting them from a Gzmblo to a Gzmbhi phenotype, thus increasing CTL tumor lytic activity. Activation of G6PD increases Gzmb+ tumor-specific CTLs and suppresses tumor growth in tumor-bearing mice. Consistent with these findings, GZMB expression level was found to correlate with increased survival in patients with epithelioid mesothelioma.ConclusionG6PD is a metabolic checkpoint in tumor-activated CTLs. The H3K9me3/G6PD/acetyl-CoA/H3K9ac/Gzmb pathway is particularly important in CTL activation and immune evasion in epithelioid mesothelioma.

H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth

“…2D ). It was reported that G6PD is active in lymphocytes [ 18 ] and plays a critical role in T cell anti-tumor function [ 28 ]. As expected, G6PD protein is detected in tumor-infiltrating lymphocytes ( Fig.…”

Classification molecular subtypes of hepatocellular carcinoma based on PRMT-related genes

“…Furthermore, the PRMT-related key genes included in our risk model have been demonstrated involved in tumor immune response regulation. For instance, G6PD was clarified participating in cytotoxic T lymphocytes (CTLs) activation and immune escape in epithelioid mesothelioma (Lu et al, 2022). KIF20A was closely associated with immune infiltration in clear cell renal cell carcinoma (ccRCC) (Ren et al, 2020).…”

Cuproptosis regulator-mediated patterns associated with immune infiltration features and construction of cuproptosis-related signatures to guide immunotherapy

“…Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme in the pentose phosphate pathway and is involved in energy generation through the maintenance of reduced NADPH co-enzyme levels ( 51 ). Because of its key metabolic role, G6PD is also involved in tumor pathogenesis where it has been reported to modulate proliferation ( 52 , 53 ), metastasis ( 54 ), chemoresistance ( 55 , 56 ), immune activation ( 57 , 58 ), and tumor ferroptosis ( 59 ). Cell division cycle-associated 8 (CDCA8) forms part of the chromosomal passenger complex (CPC) and is necessary for the stabilization of the mitotic spindle.…”