Abstract
BackgroundWe investigated the role of PD-L1 in the metabolic reprogramming of non-small cell lung cancer (NSCLC).MethodsChanges in glycolysis-related molecules and glycolytic activity were evaluated in PD-L1low and PD-L1high NSCLC cells after transfection or knockdown of PD-L1, respectively. Jurkat T-cell activation was assessed after co-culture with NSCLC cells. The association between PD-L1 and immune response-related molecules or glycolysis were analyzed in patients with NSCLC and The Cancer Genome Atlas (TCGA).ResultsTransfecting PD-L1 in PD-L1low cells enhanced hexokinase-2 (HK2) expression, lactate production, and extracellular acidification rates, but minimally altered GLUT1 and PKM2 expression and oxygen consumption rates. By contrast, knocking-down PD-L1 in PD-L1high cells decreased HK2 expression and glycolysis by suppressing PI3K/Akt and Erk pathways. Interferon-γ (IFNγ) secretion and activation marker expression was decreased in stimulated Jurkat T-cells when co-cultured with HK2-overexpressing vector-transfected tumor cells rather than empty vector-transfected tumor cells. Immunohistochemistry revealed that PD-L1 expression was positively correlated with HK2 expression in NSCLC (p < 0.001). In TCGA, HK2 exhibited a positive linear association with CD274 (PD-L1) expression (p < 0.001) but an inverse correlation with the expression of CD4, CD8A, and T-cell effector function-related genes in the CD274high rather than CD274low group. Consistently, there were fewer CD8+ T-cells in PD-L1positive/HK2high tumors compared to PD-L1positive/HK2low tumors in squamous cell carcinoma.ConclusionsPD-L1 enhances glycolysis in NSCLC by upregulating HK2, which might dampen anti-tumor immunity. PD-L1 may contribute to NSCLC oncogenesis by inducing metabolic reprogramming and immune checkpoint.
Highlights
We investigated the role of Programmed death-ligand 1 (PD-L1) in the metabolic reprogramming of non-small cell lung cancer (NSCLC)
To investigate whether PD-L1 affects the glycolysis in human NSCLC, we screened basal expression of PD-L1 and glycolysis-related molecules and glycolytic activity in several NSCLC cell lines (Additional file 3: Figure S1A-E)
HK2 expression was inversely correlated with the expression of T-cell effector response-related genes and the number of CD8+ TILs in PD-L1high NSCLCs but not PD-L1low NSCLCs. These findings suggest that the expression status of PD-L1 and HK2 in tumor cells might be involved in the regulation of immune response in the tumor microenvironment (TME) of NSCLCs
Summary
We investigated the role of PD-L1 in the metabolic reprogramming of non-small cell lung cancer (NSCLC). Methods: Changes in glycolysis-related molecules and glycolytic activity were evaluated in PD-L1low and PD-L1high NSCLC cells after transfection or knockdown of PD-L1, respectively. The association between PD-L1 and immune response-related molecules or glycolysis were analyzed in patients with NSCLC and The Cancer Genome Atlas (TCGA). By contrast, knocking-down PD-L1 in PD-L1high cells decreased HK2 expression and glycolysis by suppressing PI3K/Akt and Erk pathways. Interferon-γ (IFNγ) secretion and activation marker expression was decreased in stimulated Jurkat T-cells when co-cultured with HK2-overexpressing vector-transfected tumor cells rather than empty vectortransfected tumor cells. In TCGA, HK2 exhibited a positive linear association with CD274 (PD-L1) expression (p < 0.001) but an inverse correlation with the expression of CD4, CD8A, and T-cell effector function-related genes in the CD274high rather than CD274low group. PD-1 signaling alters T-cell metabolism by inhibiting glycolysis and amino acid metabolism and promoting lipolysis and fatty acid oxidation, thereby inhibiting effector T-cell differentiation [9]
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