Early growth response 1 as a key regulator of PD-L1 expression and immune evasion in extranodal NK/T-cell lymphoma

This study investigates the role of Early Growth Response 1 (EGR1) in extranodal natural killer/T-cell lymphoma (ENKTL) and its correlation with PD-L1 expression. Analysis of 62 ENKTL patient samples revealed that high EGR1 expression was linked to PD-L1 positivity, the immune evasion-A subtype, and early-stage disease. Although EGR1 expression was not an independent prognostic factor for overall survival, patients with higher EGR1 levels showed a trend toward better outcomes. In ENKTL cell lines (YT, SNK6), EGR1 positively regulated LMP1 and PD-L1 expression. Knockdown of EGR1 reduced PD-L1 levels, decreased PTEN, increased AKT phosphorylation, and abrogated STAT3 phosphorylation. Conversely, EGR1 overexpression enhanced PD-L1. Treatment with the histone deacetylase inhibitor entinostat upregulated both EGR1 and PD-L1, but this effect was lost in EGR1-depleted cells, indicating EGR1's necessity for HDAC inhibitor-induced PD-L1 expression. These findings reveal EGR1's pivotal role in tumor immune modulation and highlight potential combination therapies targeting EGR1, epigenetic regulators, and PD-1/PD-L1 checkpoints.