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The Correlation Between SPP1 and Immune Escape of EGFR Mutant Lung Adenocarcinoma Was Explored by Bioinformatics
Yi Zheng1, Shiying Hao2, Cheng Xiang1
1Department of Oncology, Shijiazhuang People's Hospital, Shijiazhuang, China.
Background:
Immune checkpoint inhibitors have achieved breakthrough efficacy in treating lung adenocarcinoma (LUAD) with wild-type epidermal growth factor receptor (EGFR), leading to the revision of the treatment guidelines. However, most patients with EGFR mutation are resistant to immunotherapy. It is particularly important to study the differences in tumor microenvironment (TME) between patients with and without EGFR mutation. However, relevant research has not been reported. Our previous study showed that secreted phosphoprotein 1 (SPP1) promotes macrophage M2 polarization and PD-L1 expression in LUAD, which may influence response to immunotherapy. Here, we assessed the role of SPP1 in different populations and its effects on the TME.
Methods:
We compared the expression of SPP1 in LUAD tumor and normal tissues, and in samples with wild-type and mutant EGFR. We also evaluated the influence of SPP1 on survival. The LUAD data sets were downloaded from TCGA and CPTAC databases. Clinicopathologic characteristics associated with overall survival in TCGA were assessed using Cox regression analysis. GSEA revealed that several fundamental signaling pathways were enriched in the high SPP1 expression group. We applied CIBERSORT and xCell to calculate the proportion and abundance of tumor-infiltrating immune cells (TICs) in LUAD, and compared the differences in patients with high or low SPP1 expression and wild-type or mutant EGFR. In addition, we explored the correlation between SPP1 and CD276 for different groups.
Results:
SPP1 expression was higher in LUAD tumor tissues and in people with EGFR mutation. High SPP1 expression was associated with poor prognosis. Univariate and multivariate cox analysis revealed that up-regulated SPP1 expression was independent indicator of poor prognosis. GSEA showed that the SPP1 high expression group was mainly enriched in immunosuppressed pathways. In the SPP1 high expression group, the infiltration of CD8+ T cells was lower and M2-type macrophages was higher. These results were also observed in patients with EGFR mutation. Furthermore, we found that the SPP1 expression was positively correlated with CD276, especially in patients with EGFR mutation.
Conclusion:
SPP1 levels might be a useful marker of immunosuppression in patients with EGFR mutation, and could offer insight for therapeutics.
Insights
Secreted phosphoprotein 1 (SPP1) is elevated in lung adenocarcinoma with EGFR mutations, correlating with poor prognosis and an immunosuppressive tumor microenvironment. This suggests SPP1 may indicate immunotherapy resistance in these patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint inhibitors are effective for wild-type EGFR lung adenocarcinoma (LUAD), but many EGFR-mutated patients show resistance.
- Understanding tumor microenvironment (TME) differences in EGFR-mutated LUAD is crucial for improving immunotherapy.
- Secreted phosphoprotein 1 (SPP1) was previously shown to promote M2 macrophage polarization and PD-L1 expression in LUAD.
Purpose of the Study:
- To investigate the role of SPP1 in different LUAD populations and its impact on the TME.
- To assess SPP1 expression in relation to EGFR mutation status and its association with patient prognosis.
- To explore the correlation between SPP1, immune cell infiltration, and CD276 expression in LUAD.
Main Methods:
- Analyzed SPP1 expression in LUAD tumor and normal tissues, and in samples with wild-type versus mutant EGFR using TCGA and CPTAC data.
- Evaluated SPP1's influence on overall survival via Cox regression analysis.
- Utilized Gene Set Enrichment Analysis (GSEA), CIBERSORT, and xCell to assess signaling pathways and tumor-infiltrating immune cells (TICs) in relation to SPP1 expression and EGFR status.
Main Results:
- SPP1 expression was significantly higher in LUAD tumor tissues and in patients with EGFR mutations.
- High SPP1 expression correlated with poor prognosis and was an independent indicator of survival.
- SPP1 high expression was linked to immunosuppressive pathways, reduced CD8+ T cell infiltration, and increased M2-type macrophages, particularly in EGFR-mutated LUAD. SPP1 also positively correlated with CD276.
Conclusions:
- Elevated SPP1 levels may serve as a biomarker for immunosuppression in EGFR-mutated LUAD patients.
- SPP1's role in the TME offers potential therapeutic insights for overcoming immunotherapy resistance in this patient group.
