Professor Texas A&M University Health Science Center Bryan, Texas, United States
Introduction/Rationale: Eukaryotic elongation factor 2 kinase (eEF2K) is a stress-responsive regulator of protein synthesis implicated in melanoma progression, but its role in tumor immune evasion remains poorly defined.
Methods: We investigated how eEF2K influences PD-L1 expression through modulation of Cyclin D1. We analyzed gene expression and dependency datasets from The Cancer Genome Atlas (TCGA) and Cancer Dependency Map (DepMap). Protein–protein interactions were assessed by co-immunoprecipitation. Cyclin D1 was inhibited pharmacologically with palbociclib. Immune responses were evaluated in murine B16-OVA and human A2058 melanoma models using flow cytometry and immunohistochemistry after genetic or pharmacologic modulation of eEF2K and Cyclin D1.
Results: We discovered that high eEF2K expression correlated with elevated PD-L1 levels and poorer clinical outcomes in melanoma patients. Mechanistically, eEF2K suppressed Cyclin D1 expression, while loss of eEF2K led to Cyclin D1 upregulation and consequent stabilization of PD-L1 protein. Co-immunoprecipitation confirmed a physical interaction between eEF2K and Cyclin D1. Pharmacologic inhibition of Cyclin D1 reversed PD-L1 accumulation and mitigated eEF2K-driven immune suppression. In vivo, eEF2K inhibition decreased PD-L1 expression and enhanced CD8⁺ T cell infiltration and cytotoxicity. Palbociclib treatment similarly restored cytotoxic T lymphocyte function and improved anti-tumor immunity in eEF2K knockout tumors.
Conclusion: Our findings reveal that eEF2K drives immune evasion in melanoma by stabilizing PD-L1 through Cyclin D1 suppression. Targeting the eEF2K–Cyclin D1–PD-L1 axis represents a promising strategy to augment immune checkpoint blockades and improve anti-tumor immune responses.
