Chongfan Technology
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20
2024
-
08
South China University of Technology Gao Ping team work to reveal the role of ependymal-associated proteins in coordinating tumor immune evasion and cancer progression
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Although immune checkpoint blockade (ICB) has shown promise for clinical cancer treatment, its efficacy has only been observed in a limited number of patients, and the underlying mechanisms that regulate the innate and acquired resistance of tumor cells to ICB remain poorly understood.
On August 16, 2024, Gao Ping of South China University of Technology and Zhong Xiuying of Guangdong Provincial People's Hospital jointly communicated inEMBO Journal Published online entitled“EPDR1 promotes PD-L1 expression and tumor immune evasion by inhibiting TRIM21-dependent ubiquitylation of IkappaB kinase-β” of research papers.The study sheds light on the role of EPDR1 in coordinating tumor immune evasion and cancer progression.
We found that ependymal-associated protein 1 (EPDR1) is an important tumor-intrinsic regulator of PD-L1 expression and tumor immune evasion.Aberrant expression of EPDR1 in hepatocellular carcinoma is associated with immunosuppression.Mechanically, EPDR1 binds to E3 ligase TRIM21, disrupts its interaction with I-κB kinase-B, inhibits its ubiquitination and autophagosomal degradation, and enhances NF-κb-mediated PD-L1 transcriptional activation. In addition, the authors verified that EPDR1 mediates the exhaustion of CD8 T cells and promotes tumor progression in a mouse liver cancer model. A positive correlation was also observed between the expression of EPDR1 and PD-L1 in human and mouse liver cancer samples.
The level of expression of checkpoint molecules, including PD-L1, correlates with the effectiveness of ICB treatment.While researchers recognize that PD-L1 can be regulated in a number of ways, the identification of key molecules and underlying mechanisms that drive PD-L1 expression and promote immune evasion, both within tumors and in the tumor microenvironment, still plagues researchers, hindering the wider application and maximum clinical benefit of cancer immunotherapy.
In this study, the authors worked to find potential targets for ICB therapy in liver cancer and found the underappreciated role of EPDR1 in regulating cancer progression and immune evasion.In a mouse model of HCC, tumor-endogenous EPDR1 was found to promote CD8 + t-cell exhaustion by upregulating PD-L1 transcriptional levels. Further mechanistic studies showed that EPDR1 binds to the E3 ligase TRIM21, inhibits the interaction of TRIM21 with IKBKB, stabilizes IKBKB protein and induces NF-κb-mediated PD-L1 transcriptional activation.These findings suggest that EPDR1 has important therapeutic implications in modulating anti-tumor immunity and cancer progression.
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