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. 2025 Jun 13;15(1):108.
doi: 10.1038/s41408-025-01313-w.

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

Ji Yun Lee  1 , Kui-Jin Kim  2 , Woochan Park  1 , Jeongmin Seo  1 , Minsu Kang  1 , Eun Hee Jung  1 , Sang-A Kim  1 , Koung Jin Suh  1 , Ji-Won Kim  1 , Se Hyun Kim  1 , Jeong-Ok Lee  1 , Jin Won Kim  1 , Yu Jung Kim, Keun-Wook Lee  1 , Jee Hyun Kim  1 , Soo-Mee Bang  1 , Tae Min Kim  3 , Jin Ho Paik  4
Affiliations

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

Ji Yun Lee et al. Blood Cancer J. .

Abstract

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.

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Conflict of interest statement

Competing interests: The authors declare no competing financial interests. Ethics approval and consent to participate: This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Seoul National University Bundang Hospital (B-2104-680-303). The IRB waived the requirement for patient consent due to the retrospective nature of the study.

Figures

Fig. 1
Fig. 1. Representative Histology, EBV In Situ Hybridization, and EGR1 Immunohistochemistry in ENKTL.
A–C An 82-year-old male patient with the immune evasion-A subtype and high EGR1 expression. D–F A 77-year-old female patient with the immune evasion-B subtype and low EGR1 expression. A, D Hematoxylin and eosin (H&E) staining; B, E EBV in situ hybridization; C, F EGR1 immunohistochemistry.
Fig. 2
Fig. 2. Kaplan–Meier survival curves by EGR1 expression group.
The blue line represents the EGR1 High group, indicating patients with high EGR1 expression, while the red line represents the EGR1 Low group, indicating patients with low EGR1 expression.
Fig. 3
Fig. 3. EGR1-mediated regulation of the LMP1/PD-L1 axis in ENKTL.
A Baseline expression of LMP1, RIG1, EGR1, and PD-L1 in ENKTL cell lines. B Effect of EGR1 knockdown on LMP1 and PD-L1 expression. C Flow cytometric analysis of surface PD-L1 expression following EGR1 knockdown. D EGR1 overexpression-driven enhancement of LMP1 and PD-L1 in SNK6 Cells.
Fig. 4
Fig. 4. EGR1-dependent regulation of key signaling pathways and IFN-γ-induced PD-L1 expression in ENKTL cells.
A EGR1-dependent regulation of PTEN/AKT and STAT3 signaling in ENKTL cell lines. B IFN-γ treatment effects on PD-L1 and EGR1 expression in ENKTL cell lines.
Fig. 5
Fig. 5. Entinostat-induced upregulation of PD-L1 in SNK6 cells is mediated by EGR1.
A Dose-dependent effect of entinostat on EGR1 and PD-L1 expression in SNK6 cells. B EGR1 knockdown attenuates entinostat-induced PD-L1 upregulation in SNK6 cells.
See this image and copyright information in PMC

References

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