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Yap methylation-induced FGL1 expression suppresses anti-tumor immunity and promotes tumor progression in KRAS-driven
Ji Jiang1, Pengfei Ye1, Ningning Sun2
1Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, Anhui, P. R. China.
Background:
Despite significant strides in lung cancer immunotherapy, the response rates for Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven lung adenocarcinoma (LUAD) patients remain limited. Fibrinogen-like protein 1 (FGL1) is a newly identified immune checkpoint target, and the study of related resistance mechanisms is crucial for improving the treatment outcomes of LUAD patients. This study aimed to elucidate the potential mechanism by which FGL1 regulates the tumor microenvironment in KRAS-mutated cancer.
Methods:
The expression levels of FGL1 and SET1 histone methyltransferase (SET1A) in lung cancer were assessed using public databases and clinical samples. Lentiviruses were constructed for transduction to overexpress or silence FGL1 in lung cancer cells and mouse models. The effects of FGL1 and Yes-associated protein (Yap) on the immunoreactivity of cytotoxic T cells in tumor tissues were evaluated using immunofluorescence staining and flow cytometry. Chromatin immunoprecipitation and dual luciferase reporter assays were used to study the SET1A-directed transcriptional program.
Results:
Upregulation of FGL1 expression in KRAS-mutated cancer was inversely correlated with the infiltration of CD8+ T cells. Mechanistically, KRAS activated extracellular signal-regulated kinase 1/2 (ERK1/2), which subsequently phosphorylated SET1A and increased its stability and nuclear localization. SET1A-mediated methylation of Yap led to Yap sequestration in the nucleus, thereby promoting Yap-induced transcription of FGL1 and immune evasion in KRAS-driven LUAD. Notably, dual blockade of programmed cell death-1 (PD-1) and FGL1 further increased the therapeutic efficacy of anti-PD-1 immunotherapy in LUAD patients.
Conclusion:
FGL1 could be used as a diagnostic biomarker of KRAS-mutated lung cancer, and targeting the Yap-FGL1 axis could increase the efficacy of anti-PD-1 immunotherapy.
Insights
Fibrinogen-like protein 1 (FGL1) promotes immune evasion in KRAS-mutated lung cancer by regulating the tumor microenvironment. Targeting the Yap-FGL1 pathway enhances anti-PD-1 immunotherapy efficacy in these patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Lung adenocarcinoma (LUAD) with KRAS mutations shows limited response to current immunotherapies.
- Fibrinogen-like protein 1 (FGL1) is an emerging immune checkpoint target implicated in treatment resistance.
- Understanding FGL1's role in the tumor microenvironment of KRAS-mutated LUAD is critical for therapeutic improvement.
Purpose of the Study:
- To investigate the mechanism by which FGL1 influences the tumor microenvironment in KRAS-mutated lung cancer.
- To explore the potential of FGL1 as a diagnostic biomarker and therapeutic target in KRAS-driven LUAD.
Main Methods:
- Assessed FGL1 and SET1A expression in public databases and clinical LUAD samples.
- Utilized lentiviral vectors for FGL1 manipulation in cell lines and mouse models.
- Evaluated T cell immunoreactivity via immunofluorescence and flow cytometry; investigated transcriptional regulation using ChIP and luciferase assays.
Main Results:
- FGL1 upregulation inversely correlated with CD8+ T cell infiltration in KRAS-mutated cancers.
- KRAS-ERK1/2 signaling phosphorylated SET1A, promoting its nuclear localization and Yap methylation.
- SET1A-mediated Yap nuclear sequestration enhanced FGL1 transcription, driving immune evasion; dual PD-1/FGL1 blockade improved anti-PD-1 therapy efficacy.
Conclusions:
- FGL1 serves as a potential diagnostic biomarker for KRAS-mutated lung cancer.
- Targeting the Yap-FGL1 axis represents a promising strategy to enhance anti-PD-1 immunotherapy outcomes in LUAD.
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