Journal
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume 38, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13046-019-1407-5
Keywords
Programmed cell death-ligand-1; Hexokinase 2; Glycolysis; Non-small cell lung cancer; Tumor microenvironment
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Funding
- Seoul National University Hospital Research Fund [800-20160023]
- Seoul National University (SNU) [0320170160 [2017-1312]]
- Basic Science Research Program through the National Research Foundation (NRF) - Ministry of Education, Science and Technology (MEST), Republic of Korea [NRF-2016R1D1A1B01015964]
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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-gamma (IFN gamma) 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.
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