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

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.