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Mitochondrial Pathway Signature (MitoPS) predicts immunotherapy response and reveals NDUFB10 as a key immune
Pengpeng Zhang1,2, Mengzhe Zhang1, Jianlan Liu3
1Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Background:
Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer. Although immune checkpoint inhibitors (ICIs) have brought new treatment options for advanced patients, a considerable proportion still shows limited response. Mitochondrial dysfunction plays a crucial role in tumor development and immune evasion, but its regulatory mechanisms in LUAD immune microenvironment remain unclear.
Methods:
We integrated 149 mitochondria-related pathways (1,136 coding proteins) to develop and validate the Mitochondrial Pathway Signature (MitoPS) using machine learning approaches across seven independent LUAD cohorts (n=1,231). The system was systematically compared with 129 published LUAD prognostic signatures and validated in seven immunotherapy cohorts (n=451). Multiomics analysis, immunofluorescence staining, and experimental validation were performed to investigate its molecular mechanism.
Results:
MitoPS demonstrated consistent predictive performance across validation cohorts, with high scores indicating poor prognosis, outperforming 129 existing prognostic models. In immunotherapy cohorts, MitoPS reliably predicted treatment response and prognosis. Immune microenvironment analysis revealed that low MitoPS scores correlated with higher immune cell infiltration and active immune function. Mechanistic studies identified mitochondria-related gene NDUFB10 as a core gene of MitoPS (r=0.38, p<0.05), where its high expression was significantly associated with immune desert phenotype and worse prognosis. Functional experiments confirmed that NDUFB10 knockdown significantly enhanced ICIs therapy and increased GZMB+CD8+T cell infiltration, indicating NDUFB10's crucial role in regulating tumor immune microenvironment and immunotherapy response.
Conclusion:
The MitoPS scoring system reliably predicts prognosis and immunotherapy response in patients with LUAD, providing a novel reference for clinical decision-making. Furthermore, its core gene NDUFB10 regulates tumor immune microenvironment, offering a potential therapeutic target for improving immunotherapy outcomes.
Insights
A new Mitochondrial Pathway Signature (MitoPS) predicts lung adenocarcinoma prognosis and immunotherapy response. Its core gene, NDUFB10, influences the tumor immune microenvironment and may be a therapeutic target.
Area of Science:
- Oncology
- Immunology
- Mitochondrial Biology
Background:
- Lung adenocarcinoma (LUAD) is a common cancer with limited response to immune checkpoint inhibitors (ICIs).
- Mitochondrial dysfunction is implicated in tumor development and immune evasion, but its role in LUAD's immune microenvironment is unclear.
Purpose of the Study:
- To develop and validate a novel prognostic and predictive signature for LUAD based on mitochondrial pathways.
- To investigate the molecular mechanisms underlying the signature's association with prognosis and immunotherapy response.
Main Methods:
- Integrated 149 mitochondria-related pathways (1,136 proteins) to create the Mitochondrial Pathway Signature (MitoPS) using machine learning.
- Validated MitoPS across seven LUAD cohorts (n=1,231) and seven immunotherapy cohorts (n=451).
- Performed multiomics analysis, immunofluorescence, and experimental validation, focusing on the core gene NDUFB10.
Main Results:
- MitoPS demonstrated consistent predictive performance for prognosis and immunotherapy response, outperforming existing models.
- Low MitoPS scores correlated with increased immune cell infiltration and active immune function.
- High expression of NDUFB10, a core MitoPS gene, was linked to an immune desert phenotype, worse prognosis, and impaired immunotherapy response; NDUFB10 knockdown enhanced ICI therapy and T-cell infiltration.
Conclusions:
- The MitoPS scoring system reliably predicts LUAD patient prognosis and immunotherapy outcomes.
- NDUFB10 plays a critical role in regulating the tumor immune microenvironment and immunotherapy response, presenting a potential therapeutic target.
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