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

Journal of Experimental & Clinical Cancer Research

Ji-Young Jang¹  Dae Seog Heo¹  Tae Min Kim¹  Miso Kim¹  Bhumsuk Keam¹  Chan-Young Ock²  Jin Chul Paeng³  Young A. Kim⁴  Doo Hyun Chung⁴  Yoon Kyung Jeon⁴  Dohee Kwon⁴  Sehui Kim⁴  Jaemoon Koh⁴ 

[1] Cancer Research Institute, Seoul National University;Department of Internal Medicine, Seoul National University College of Medicine;Department of Nuclear Medicine, Seoul National University Hospital, Seoul National University College of Medicine;Department of Pathology, Seoul National University College of Medicine;

关键词: Programmed cell death-ligand-1;    Hexokinase 2;    Glycolysis;    Non-small cell lung cancer;    Tumor microenvironment;   

DOI  :  10.1186/s13046-019-1407-5

来源: DOAJ

【 摘 要 】

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 CD274 high rather than CD274 low 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.

【 授权许可】

Unknown