1. Academic Validation
  2. 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

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

  • Onco Targets Ther. 2018 Oct 18;11:7229-7243. doi: 10.2147/OTT.S180505.
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 Niu 1 2
Affiliations

Affiliations

  • 1 Key Laboratory, Department of Urology and Andrology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China, liangye82812@163.com.
  • 2 Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China, niuht0532@126.com; liangye82812@163.com.
  • 3 Department of Vascular Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China.
Abstract

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

PD-L1; T cells; bladder cancer cells; co-culture; glutaminolysis.

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