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Background  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-L1 low  and PD-L1 high  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).    Results  Transfecting  PD-L1  in PD-L1 low  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-L1 high  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  CD274  high  rather than  CD274  low  group. Consistently, there were fewer CD8 +  T-cells in PD-L1 positive /HK2 high  tumors compared to PD-L1 positive /HK2 low  tumors in squamous cell carcinoma.    Conclusions  PD-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.

journal of experimental and clinical cancer research

Programmed cell death ligand-1-mediated enhancement of hexokinase 2 expression is inversely related to T-cell effector gene expression in non-small-cell lung cancer