Abstract
Background: Tumor immune microenvironment plays a vital role in tumorigenesis and progression of gastric cancer (GC), but potent immune biomarkers for predicting the prognosis have not been identified yet.Methods: At first, RNA-sequencing and clinical data from The Cancer Genome Atlas (TCGA) were mined to identify an immune-risk signature using least absolute shrinkage and selection operator (LASSO) regression and multivariate stepwise Cox regression analyses. Furthermore, the risk score of each sample was calculated, and GC patients were divided into high-risk group and low-risk group based on their risk scores. Subsequently, the performance of this signature, including the correlation with overall survival (OS), clinical features, immune cell infiltration, and immune response, has been tested in GC data from TCGA database and Gene Expression Omnibus (GSE84437), respectively.Results: An immune signature composed of four genes (MAGED1, ACKR3, FZD2, and CTLA4) was constructed. The single sample gene set enrichment analysis (ssGSEA) indicated that activated CD4+/CD8+ T cell, activated dendritic cell, and effector memory CD8+ T cell prominently increased in the low-risk group, showing relatively high immune scores and low stromal scores. Further GSEA analysis indicated that TGF-β, Ras, and Rap1 pathways were activated in the high-risk group, while Th17/Th1/Th2 differentiation, T cell receptor and PD-1/PD-L1 checkpoint pathways were activated in the low-risk group. Low-risk patients presented higher tumor mutation burden (TMB) and expression of HLA-related genes. The immune-associated signature showed an excellent predictive ability for 2-, 3-, and 5-year OS in GC.Conclusion: The immune-related prognosis model contributes to predicting the prognosis of GC patients and providing valuable information about their response to immunotherapy using integrated bioinformatics methods.
Highlights
MATERIALS AND METHODSGastric cancer (GC) is a common digestive tract tumor and the third leading cause of cancer-related deaths (Bray et al, 2018)
The single sample gene set enrichment analysis indicated that activated CD4+/CD8+ T cell, activated dendritic cell, and effector memory CD8+ T cell prominently increased in the low-risk group, showing relatively high immune scores and low stromal scores
Further gene set enrichment analysis (GSEA) analysis indicated that TGF-β, Ras, and Rap1 pathways were activated in the high-risk group, while Th17/Th1/Th2 differentiation, T cell receptor and PD-1/PD-L1 checkpoint pathways were activated in the low-risk group
Summary
MATERIALS AND METHODSGastric cancer (GC) is a common digestive tract tumor and the third leading cause of cancer-related deaths (Bray et al, 2018). Tumor immune microenvironment (TIM) is closely related to the tumorigenesis and tumor progression, as well as resistance to immunotherapy (Bindea et al, 2013; Quail and Joyce, 2013; Fridman et al, 2017). The oncologists focus on activating immune responses, screening highly specific immune biomarkers, and exploring immune regulatory mechanisms to restore dysregulated immune microenvironment and improve survival outcomes (Eso and Seno, 2020). There is still no effective biomarker to predict sensitivity or resistance to ICIs. It is far from enough to fully understand the roles of tumor immune landscape in GC. Tumor immune microenvironment plays a vital role in tumorigenesis and progression of gastric cancer (GC), but potent immune biomarkers for predicting the prognosis have not been identified yet
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