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The elevated glutaminolysis of bladder cancer and T cells in a simulated tumor microenvironment contributes to the up-regulation of PD-L1 expression by interferon-γ

Authors Wang LP, Yang XC, Li D, Liang ZJ, Chen YB, Ma GF, Wang YH, Li YX, Liang Y, Niu HT

Received 17 July 2018

Accepted for publication 10 September 2018

Published 18 October 2018 Volume 2018:11 Pages 7229—7243

DOI https://doi.org/10.2147/OTT.S180505

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Andrew Yee

Peer reviewer comments 2

Editor who approved publication: Dr Faris Farassati


Liping Wang,1,* Xuecheng Yang,2,* Dan Li,1 Zhijuan Liang,1 Yuanbin Chen,1 Guofeng Ma,2 Yonghua Wang,2 Yongxin Li,3 Ye Liang,1 Haitao Niu1,2

1Key Laboratory, Department of Urology and Andrology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China; 2Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China; 3Department of Vascular Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China

*These authors contributed equally to this work

Background: Metabolic reprogramming occurs in the tumor microenvironment and influences the survival and function of tumor and immune cells. Interferon-γ (IFN-γ) produced by T cells up-regulates PD-L1 expression in tumors. However, reports regarding the relationship between nutrient metabolism and the up-regulation of PD-L1 expression are lacking.
Materials and methods: In this paper, we analyzed the metabolic changes in T cells and bladder cancer cells in a simulated tumor microenvironment to provide evidence regarding their relevance to PD-L1 up-regulation.
Results: The glutaminolysis was increased in both activated T cells and glucose-deprived T cells. IFN-γ production by T cells was decreased in a glucose-free medium and severely decreased when cells were simultaneously deprived of glutamine. Furthermore, the glutaminolysis of the bladder cancer cells under glucose deprivation exhibited a compensatory elevation. The glucose concentration of T cells co-cultured with bladder cancer cells was decreased and T cell proliferation was reduced, but IFN-γ production and glutaminolysis were increased. However, in bladder cancer cells, the elevation in glutaminolysis under co-culture conditions did not compensate for glucose deprivation because the glucose concentration in the culture medium did not significantly differ between the cultures with and without T cells. Our data also show that inhibiting glutamine metabolism in bladder cancer cells could reduce the elevation in PD-L1 expression induced by IFN-γ.
Conclusion: In a simulated tumor microenvironment, elevated glutaminolysis may play an essential role in IFN-γ production by T cells, ultimately improving the high PD-L1 expression, and also directly contributing to producing more PD-L1 in bladder cancer cells.

Keywords: T cells, bladder cancer cells, glutaminolysis, PD-L1, co-culture

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