KRAS mutation promotes immune escape of lung adenocarcinoma via ZNF24/SLC7A5/PD-L1 axis
Leilei Li1,2, Qiang Feng2, Ya Jiang2
1Graduate School, Kunming Medical University, Kunming, Yunnan, 650500, People's Republic of China.
Background:
The imbalance of immune checkpoint molecules leads to immune escape of tumor cells. It has been established that KRAS mutation plays a key role in regulating PD-L1 expression of lung adenocarcinoma. However, the specific mechanism by which KRAS mutation regulates PD-L1 expression still needs further been clarified.
Methods:
The relationship of KRAS mutation and ZNF24, SLC7A5 and PD-L1 expression in human lung adenocarcinoma tissues and cell lines were analyzed using relative assays. The effects of KRAS mutation on CD8+ T cell-dependent anti-tumor immunity via the ZNF24/SLC7A5/PD-L1 axis were analyzed through in vitro and in vivo experiments. Additionally, we examined whether and how targeting ZNF24 inhibits KRAS mutation-induced PD-L1 expression and evaluated the effect of ZNF24 inhibition and PD-L1 blocking on CD8+ T cell-dependent anti-tumor immunity.
Results:
Our results found that KRAS mutation increases the expression of PD-L1 through the ZNF24/SLC7A5 axis and simultaneously inhibits the activation of CD8+ T cells in lung adenocarcinoma. Importantly, we discovered that Daptomycin (DAPT) binds to ZNF24 and inactivates it, representing the first reported inhibitor of ZNF24. DAPT combined with Anti PD-L1 monoclonal antibody may enhance CD8+ T cell-dependent anti-tumor immunity in KRAS mutated lung adenocarcinoma.
Conclusion:
Our study provides the first evidence that KRAS mutation promotes immune escape in lung adenocarcinoma through the ZNF24/SLC7A5/PD-L1 axis.
Insights
KRAS mutation drives lung adenocarcinoma immune escape via the ZNF24/SLC7A5/PD-L1 pathway. Targeting ZNF24 with Daptomycin and PD-L1 blockade may boost anti-tumor immunity in these patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint molecule imbalance facilitates tumor immune evasion.
- KRAS mutations are known regulators of PD-L1 expression in lung adenocarcinoma.
- The precise mechanisms linking KRAS mutations to PD-L1 regulation require further elucidation.
Purpose of the Study:
- To investigate the mechanism by which KRAS mutations regulate PD-L1 expression in lung adenocarcinoma.
- To explore the role of the ZNF24/SLC7A5 axis in this process.
- To evaluate therapeutic strategies targeting this pathway for enhanced anti-tumor immunity.
Main Methods:
- Analysis of KRAS mutation, ZNF24, SLC7A5, and PD-L1 expression in lung adenocarcinoma tissues and cell lines.
- In vitro and in vivo experiments assessing the impact of KRAS mutations on CD8+ T cell immunity via the ZNF24/SLC7A5/PD-L1 axis.
- Evaluation of ZNF24 inhibition and PD-L1 blockade effects on anti-tumor immunity.
Main Results:
- KRAS mutation upregulates PD-L1 expression via the ZNF24/SLC7A5 axis, suppressing CD8+ T cell activation in lung adenocarcinoma.
- Daptomycin (DAPT) was identified as the first ZNF24 inhibitor, binding and inactivating ZNF24.
- Combination therapy with DAPT and anti-PD-L1 antibody shows potential to enhance CD8+ T cell-mediated anti-tumor immunity.
Conclusions:
- KRAS mutation promotes immune escape in lung adenocarcinoma through the ZNF24/SLC7A5/PD-L1 axis.
- This study identifies ZNF24 as a key mediator in KRAS-driven PD-L1 expression.
- Targeting the ZNF24/SLC7A5/PD-L1 axis offers a promising therapeutic strategy for KRAS-mutated lung adenocarcinoma.
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