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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

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Authors
Kim, Sehui; Jang, Ji-Young; Koh, Jaemoon; Kwon, Dohee; Kim, Young A; Paeng, Jin Chul; Ock, Chan-Young; Keam, Bhumsuk; Kim, Miso; Kim, Tae Min; Heo, Dae Seog; Chung, Doo Hyun; Jeon, Yoon Kyung
Issue Date
2019-11-12
Publisher
BMC
Citation
Journal of Experimental & Clinical Cancer Research, 38(1):462
Keywords
Programmed cell death-ligand-1Hexokinase 2GlycolysisNon-small cell lung cancerTumor microenvironment
Abstract
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-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).

Results
Transfecting 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.

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.
ISSN
1756-9966
Language
English
URI
https://doi.org/10.1186/s13046-019-1407-5

http://hdl.handle.net/10371/164735
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College of Medicine/School of Medicine (의과대학/대학원)Pathology (병리학전공)Journal Papers (저널논문_병리학전공)
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