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EPDR1 promotes PD-L1 expression and antitumor immune evasion by inhibiting TRIM21-dependent ubiquitylation if IKBKB.

ABSTRACT: While immune checkpoint blockade (ICB) has shown promise for clinical cancer therapy, its efficacy has only been observed in a limited subset of patients and the underlying mechanisms regulating innate and acquired resistance to ICB of tumor cells is poorly understood. Here, we identified EPDR1 as an important intrinsic tumor regulator of PD-L1 expression and the antitumor T-cell response that inhibits TRIM21-dependent ubiquitylation of IKBKB. Mechanistically, EPDR1 binds to TRIM21 and disrupts its interaction with IKBKB, which suppresses the ubiquitylation and autophagosome degradation of the IKBKB protein and thus enhances NF-κB-mediated transcriptional activation of PD-L1. We further confirmed through a mouse liver cancer model that EPDR1 mediates the exhaustion of CD8+ T cells and promotes tumor progression. In addition, we observed a positive correlation between EPDR1 and PD-L1 expression in both human and mouse liver cancer samples. Collectively, our study reveals an unappreciated role of EPDR1 in orchestrating tumor immune evasion and cancer progression, suggesting that targeting EPDR1-TRIM21 is a potential strategy for cancer immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250169 | GEO | 2024/06/29

REPOSITORIES: GEO

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Project description:Introduction Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC. Methods HCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses. Results Immunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3+ and LAG-3+CD8+ cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3+ cell proportion to the total CD8+ cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8+ cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3+CD8+ cell proportion was significantly associated with responses to ICB regardless of viral status. Conclusion Immunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting.

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EPDR1 promotes PD-L1 expression and antitumor immune evasion by inhibiting TRIM21-dependent ubiquitylation if IKBKB.

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