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Updated: May 28, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Molecular Subtyping and Therapeutic Targeting of IFNG-Driven Immunogenic Cell Death in Lung Adenocarcinoma
Lifeng Li1,2,3,4, Yaqi Yang1,2, Mengle Peng5,6
1National Engineering Laboratory for Internet Medical Systems and Applications, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
Background:
Immunogenic cell death (ICD) can be triggered by various therapies to induce anti-tumor immune responses, significantly enhancing treatment effectiveness, and is widely utilized in tumor immunotherapy.
Methods:
LUAD data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) validated ICD-related molecular subtypes via consensus clustering. Clinical features, ICD genes, driver genes, mutations, tumor microenvironment, immune checkpoints, and drug sensitivity were compared. RT-qPCR, Western blot, immunofluorescence, ELISA, flow cytometry, and tube formation assays validated findings.
Results:
Differential expression of 33 ICD genes was observed between tumor and normal tissues. These genes were clustered into two groups via consensus clustering and validated with GEO data. Prognostic analysis indicated superior outcomes in cluster 2 across TCGA and GEO cohorts. Significant disparities in clinicopathological characteristics like stage, gender, and age were noted between subtypes. Cluster 2 exhibited heightened expression of ICD-related genes, driver genes, immune checkpoints, and immune cells. Cluster 2 also showed increased sensitivity to chemotherapy drugs. IFNG overexpression in A549 and H1299 cells induced CRT exposure, HMGB1 release, and ATP secretion, thereby promoting dendritic cell maturation and enhancing CD8+ T cell function. Additionally, IFNG boosted tumor angiogenesis via HMGB1 pathways, which could be mitigated by HMGB1 inhibition.
Conclusion:
Identification of novel ICD-related molecular subtypes holds promise for guiding personalized therapies, assessing prognosis, and predicting immunotherapy efficacy in LUAD. IFNG emerges as a potential prognostic biomarker and therapeutic target, influencing both the tumor microenvironment and angiogenesis. These findings offer new insights into therapeutic strategies targeting IFNG-mediated pathways in LUAD.
Insights
Researchers identified two novel immunogenic cell death (ICD) molecular subtypes in lung adenocarcinoma (LUAD). One subtype shows better prognosis and increased sensitivity to chemotherapy, offering insights for personalized LUAD treatment.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immunogenic cell death (ICD) therapies enhance anti-tumor immunity and are crucial in tumor immunotherapy.
- Understanding ICD's role is key to improving cancer treatment effectiveness.
Purpose of the Study:
- To identify novel ICD-related molecular subtypes in lung adenocarcinoma (LUAD).
- To analyze the clinical significance, tumor microenvironment, and therapeutic sensitivity of these subtypes.
- To investigate the role of Interferon-gamma (IFNG) in LUAD.
Main Methods:
- Consensus clustering of LUAD data from TCGA and GEO to define ICD molecular subtypes.
- Comparative analysis of clinical features, gene expression, mutations, tumor microenvironment, immune checkpoints, and drug sensitivity between subtypes.
- In vitro experiments (RT-qPCR, Western blot, immunofluorescence, ELISA, flow cytometry, tube formation assays) to validate IFNG's function.
Main Results:
- Two distinct ICD molecular subtypes were identified, with Cluster 2 demonstrating superior prognosis across cohorts.
- Cluster 2 exhibited significant differences in clinicopathological characteristics, heightened expression of ICD genes, driver genes, immune checkpoints, and immune cells.
- Cluster 2 showed increased sensitivity to chemotherapy drugs. IFNG overexpression promoted ICD, dendritic cell maturation, CD8+ T cell function, and angiogenesis, which could be modulated by HMGB1 inhibition.
Conclusions:
- Novel ICD-related molecular subtypes in LUAD can guide personalized therapies, prognosis assessment, and immunotherapy efficacy prediction.
- IFNG is a potential prognostic biomarker and therapeutic target in LUAD, impacting the tumor microenvironment and angiogenesis.
- Findings provide insights into IFNG-mediated pathway-targeted therapeutic strategies for LUAD.
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