Envafolimab Inhibits the Growth of Gastric Cancer Cells with Low PD-L1 Expression through the DDX20/NF-κB/TNF-α
Zhuanxia Dong1, Zefeng Yang2, Jing Ren3
1Shanxi Medical University, Taiyuan, Shanxi 030001, China.
Background:
The mechanism of action of envafolimab (also known as KN035), a programmed death ligand 1 (PD-L1) inhibitor, in gastric adenocarcinoma patients with low PD-L1 expression is not well understood.
Objectives:
The objective of this study was to explore the underlying mechanism of envafolimab in gastric cancer with low PD-L1 expression.
Methods:
Cytotoxicity and proliferation were evaluated by a CCK8 assay. Transwell assays were used to detect the migration and invasion ability of gastric cancer cells. The effect of envafolimab on the apoptosis of gastric cancer cells was detected by flow cytometry. The effect of envafolimab on gastric cancer cells with low PD-L1 expression was investigated via proteomics and bioinformatics analysis.
Results:
A total of 19 patients with advanced gastric adenocarcinoma who received envafolimab monotherapy or combination therapy were reviewed. Among them, 4 patients had low PD-L1 expression, the objective response rate (ORR) was 75% (3/4), and the disease control rate (DCR) was 100% (4/4). In vitro experiments showed that envafolimab inhibited the proliferation, invasion, and migration of gastric cancer cells with low expression of PD-L1 and induced cell apoptosis. DDX20 may be the target of envafolimab in gastric cancer cells, and it is related to the NF-κB signaling pathway. Western blot results showed that the protein expressions of DDX20, NF-κB p65, and TNF-α in gastric cancer cells were decreased after adding envafolimab. Furthermore, the DDX20 gene was silenced by small interfering RNA to further study the effect of DDX20 on PDL1 low expression in gastric cancer cells.
Conclusion:
This study confirmed that envafolimab could inhibit the growth of gastric cancer cells with low PD-L1 expression by down-regulating DDX20 expression and regulating the NF- κB/TNF-α signaling pathway.
Insights
Envafolimab inhibits gastric cancer growth in patients with low PD-L1 expression by targeting DDX20 and regulating the NF-κB/TNF-α pathway. This mechanism enhances treatment efficacy for this patient subgroup.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- The mechanism of action for envafolimab, a PD-L1 inhibitor, in gastric cancer patients with low PD-L1 expression remains unclear.
- Understanding this mechanism is crucial for optimizing treatment strategies.
Purpose of the Study:
- To elucidate the underlying mechanism of envafolimab in gastric cancer with low PD-L1 expression.
- To identify potential molecular targets and pathways affected by envafolimab.
Main Methods:
- In vitro assays (CCK8, Transwell, flow cytometry) assessed cytotoxicity, proliferation, migration, invasion, and apoptosis.
- Proteomics, bioinformatics, and Western blot analyses investigated molecular changes.
- Gene silencing (siRNA) of DDX20 was employed to confirm its role.
Main Results:
- Envafolimab demonstrated significant anti-tumor activity in vitro, inhibiting proliferation and invasion while inducing apoptosis in low PD-L1 gastric cancer cells.
- Proteomic and Western blot analyses identified DDX20 as a potential target, with its downregulation correlating with NF-κB and TNF-α pathway inhibition.
- Clinical review showed a 75% ORR and 100% DCR in patients with low PD-L1 expression receiving envafolimab.
Conclusions:
- Envafolimab inhibits gastric cancer cell growth with low PD-L1 expression by downregulating DDX20.
- The observed effects are mediated through the regulation of the NF-κB/TNF-α signaling pathway.
- DDX20 is a key mediator of envafolimab's efficacy in this specific patient population.
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