Regulatory mechanisms of PD-L1 expression under prolonged glucose deprivation: lack of involvement of the ER stress response

초록

The tumor microenvironment poses significant challenges for cancer cell survival and growth but can also drive more aggressive tumor behavior, including resistance to anticancer treatments and immune evasion. The impact of glucose deprivation within the tumor microenvironment on anticancer immune responses, particularly its role in regulating PD-L1 expression, remains poorly understood. Studies have reported conflicting effects of short-term (24-hour) glucose deprivation on PD-L1 expression in renal and hepatocellular carcinoma cells (Cell Death Discov 7:15, 2021; Sci Rep 14:1751, 2024). Moreover, the mechanisms regulating PD-L1 expression under prolonged glucose deprivation conditions are not well characterized. In A549 lung adenocarcinoma cells, short-term glucose deprivation (< 7 days) did not significantly alter PD-L1 protein levels, despite an increase in BiP protein level. However, prolonged glucose deprivation (≥ 4 weeks) progressively increased PD-L1 mRNA and protein levels, including cell surface PD-L1, with a corresponding resistance to cytotoxic T lymphocyte (CTL)-mediated apoptosis including granzyme B-induced cell death. Our findings demonstrated that Janus kinase 2 (JAK2), histone deacetylase 2/6 (HDAC2/6), and EGFR/MEK/ERK signaling critically contribute to enhanced PD-L1 expression under prolong glucose deprivation. Mechanistically, JAK2 inhibition reduced PD-L1 protein level by promoting its proteasomal degradation, whereas suppression of HDAC6 and EGFR signaling primarily modulated PD-L1 transcription, independent of proteasome activity. Notably, no correlation was observed between PD-L1 regulation and the activity of BiP or IRE1α-XBP1 signaling, indicating that ER stress response is not involved in this process. In summary, prolonged glucose deprivation enhances PD-L1 expression through dual mechanisms: JAK2-mediated stabilization of PD-L1 protein and transcriptional activation regulated by HDAC6 and EGFR signaling (supported by 2022R1F1A1071397).