Effect of long-term hypoglycemic condition on tumor-specific cytotoxic T lymphocyte responses and PD-L1 expression

초록

The solid tumor microenvironment is unfavorable for the survival and proliferation of cancer cells but promotes more aggressive tumor progression including resistance to anticancer therapies. Research on the impact of glucose deprivation within the tumor microenvironment on anticancer immune responses is limited, particularly studies on whether long-term glucose deprivation regulates PD-L1 expression. In A549 cells, the protein levels of BiP and levels of PD-L1 mRNA and protein gradually increased inversely correlated with glucose concentrations following a minimum deprivation period of four weeks. In contrast, within less than seven days of glucose deprivation, the levels of BiP protein increased, while the levels of PD-L1 protein remained unchanged. Long-term glucose deprivation resulted in an increase of cell surface PD-L1 protein levels, and a decrease of cancer cell death by cytotoxic T lymphocytes (CTL) as well as granzyme B-induced apoptosis. Janus kinase (JAK) and histone deacetylase (HDAC) were involved in PD-L1 expression induced by long-term glucose deprivation. The increase in PD-L1 protein level under the condition was abrogated by inhibition of JAK1/2/3, while increase in PD-L1 mRNA level was unaffected. In contrast, the inhibition of HDAC1/2/6 almost abolished the increase in PD-L1 mRNA and protein levels under glucose-deprived conditions. The suppression of PD-L1 protein expression induced by JAK2 inhibition was reversed by proteasome inhibition, whereas the effect induced by HDAC6 inhibition was nearly unaffected regardless of proteasome inhibition. Taken together, these data suggest that long-term glucose deprivation increases PD-L1 expression, thereby attenuating tumor-specific CTL response, and that it increases PD-L1 expression by inhibiting proteasomal degradation of PD-L1 through JAK2 activation and inducing PD-L1 transcription through HDAC6 activation. This research was supported by the National Research Foundation of Korea (2022R1F1A1071397).