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Author Spotlight: Unveiling Transmembrane Protein Family-Related Markers in Gastric Cancer and Implications for Targeted Therapies
Published on: September 15, 2023
Comprehensive Analyses of Immune Subtypes of Stomach Adenocarcinoma for mRNA Vaccination
Weiqiang You1,2, Jian Ouyang3,4, Zerong Cai1,2
1Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Background:
Although messenger RNA (mRNA) vaccines have unique advantages against multiple tumors, mRNA vaccine targets in stomach adenocarcinoma (STAD) remain unknown. The potential effectiveness of mRNA vaccines is closely associated with the tumor immune infiltration microenvironment. The present study aimed to identify tumor antigens of STAD as mRNA vaccine targets and systematically determine immune subtypes (ISs) of STAD that might be suitable for immunotherapy.
Methods:
Gene expression profiles and clinical data of patients with gastric cancer were downloaded from The Cancer Genome Atlas (TCGA; n = 409) and the Gene Expression Omnibus (GEO; n = 433), and genomic data were extracted from cBioPortal. Differential gene expression was analyzed using the limma package, genetic alterations were visualized using maftools, and prognosis was analyzed using ToPP. Correlations between gene expression and immune infiltration were calculated using TIMER software, and potential ISs were identified using ConsensusClusterPlus. Functional enrichment was analyzed in clusterProfiler, and r co-expression networks were analyzed using the weighted gene co-expression network analysis (WGCNA) package in R.
Results:
Overexpression of the prognostic and highly mutated antigens ADAMTS18, COL10A1, PPEF1, and STRA6 was associated with infiltration by antigen-presenting cells in STAD. Five ISs (IS1-IS5) in STAD with distinct prognoses were developed and validated in TCGA and GEO databases. The tumor mutational burden and molecular and clinical characteristics significantly differed among IS1-IS5. Both IS1 and IS2 were associated with a high mutational burden, massive infiltration by immune cells, especially antigen-presenting cells, and better survival compared with the other subtypes. Both IS4 and IS5 were associated with cold immune infiltration and correlated with advanced pathological stages. We analyzed the immune microenvironments of five subtypes of immune modulators and biomarkers to select suitable populations for mRNA vaccination and established four co-expressed key modules to validate the characteristics of the ISs. Finally, the correlation of these four mRNA vaccine targets with the transcription factors of DC cells, including BATF3, IRF4, IRF8, ZEB2, ID2, KLF4, E2-2, and IKZF1, were explored to reveal the underlying mechanisms.
Conclusions:
ADAMTS18, COL10A1, PPEF1, and STRA6 are potential mRNA vaccine candidates for STAD. Patients with IS1 and IS2 are suitable populations for mRNA vaccination immunotherapy.
Insights
This study identifies four novel messenger RNA (mRNA) vaccine targets—ADAMTS18, COL10A1, PPEF1, and STRA6—for stomach adenocarcinoma (STAD). Patients with immune subtypes IS1 and IS2 show promise for mRNA vaccination immunotherapy due to enhanced immune cell infiltration.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Messenger RNA (mRNA) vaccines offer unique advantages for treating multiple tumors.
- Identifying specific mRNA vaccine targets for stomach adenocarcinoma (STAD) is crucial for therapeutic development.
- The tumor immune microenvironment significantly influences the effectiveness of mRNA vaccines.
Purpose of the Study:
- To identify potential mRNA vaccine targets in stomach adenocarcinoma (STAD).
- To systematically classify STAD into distinct immune subtypes (ISs) for immunotherapy suitability.
- To explore the correlation between identified targets and immune cell transcription factors.
Main Methods:
- Utilized gene expression profiles and clinical data from TCGA and GEO databases for STAD patients.
- Analyzed differential gene expression, genetic alterations, and prognosis.
- Correlated gene expression with immune infiltration using TIMER and identified ISs via ConsensusClusterPlus.
- Performed functional enrichment analysis and weighted gene co-expression network analysis (WGCNA).
Main Results:
- Identified ADAMTS18, COL10A1, PPEF1, and STRA6 as overexpressed prognostic antigens associated with antigen-presenting cell infiltration in STAD.
- Classified STAD into five distinct immune subtypes (IS1-IS5) with varying prognoses, tumor mutational burden, and immune infiltration levels.
- IS1 and IS2 exhibited high mutational burden, significant immune cell infiltration, and favorable survival, indicating suitability for immunotherapy.
- IS4 and IS5 were characterized by cold immune infiltration and advanced pathological stages.
Conclusions:
- ADAMTS18, COL10A1, PPEF1, and STRA6 are promising mRNA vaccine candidates for STAD.
- STAD patients within immune subtypes IS1 and IS2 represent a suitable population for mRNA vaccination immunotherapy.
- Further exploration of the correlation between vaccine targets and dendritic cell transcription factors provides mechanistic insights.
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