ABSTRACT: Immunotherapy is remarkably affected by the immune environment of the principal tumor. Nonetheless, the immune environment's clinical relevance in stage IV gastric cancer (GC) is largely unknown. The gene expression profiles of 403 stage IV GC patients in the three cohorts: GEO (Gene Expression Omnibus, GSE84437 (n=292) and GSE62254 (n=77), and TCGA (The Cancer Genome Atlas, n=34) were used in the present study. Using four publicly available stage IV GC expression datasets, 29 immune signatures were expression profiled, and on this basis, we classified stage IV GC. The classification was conducted using the hierarchical clustering method. Three stage IV GC subtypes L, M, and H were identified representing low, medium, and high immunity, respectively. Immune correlation analysis of these three types revealed that Immune H exhibited a better prognostic outcome as well as a higher immune score compared with other subtypes. There was a noticeable difference in the three subgroups of HLA genes. Further, on comparing with other subtypes, CD86, CD80, CD274, CTLA4, PDCD1, and PDCD1LG2 had higher expression in the Immunity H subtype. In stage IV GC, potentially positive associations between immune and pathway activities were displayed, due to the enrichment of pathways including TNF signaling, Th-17 cell differentiation, and JAK-STAT signaling pathways in Immunity H vs Immunity L subtypes. External cohorts from TCGA cohort ratified these results. The identification of stage IV GC subtypes has potential clinical implications in stage IV GC treatment.
