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.
Highlights
gastric cancer (GC), being the third most common reason for worldwide deaths due to cancer and the fifth in incidence among common cancers, exerts increasing the burden on healthcare [1,2]
The gene expression profiles and clinical data of stage IV GC were retrospectively collected from the GEO (Gene Expression Omnibus) (GSE84437 and GSE62254 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi)
For each stage IV GC dataset (GSE84437, GSE62254, and TCGA), the single sample GSEA (ssGSEA) score [20,21] was adopted to the 29 immune signatures in each stage IV GC sample to quantify the levels of enrichment
Summary
GC (gastric cancer), being the third most common reason for worldwide deaths due to cancer and the fifth in incidence among common cancers, exerts increasing the burden on healthcare [1,2]. PALM (Para-aortic lymph node metastasis)-characterized stage IV GC has a very poor prognosis even after isolated surgical treatment [3]. The primary approach for stage IV GC therapy remains palliative chemotherapy. The OS (overall median survival) rate of GC patients in stage IV remains at 9–11 months despite the recent advancements in chemotherapy [4]. Only few GC patients have benefited from the immune therapy. It is urgent to explore new therapeutic strategies for targeting stage IV GC patients. In the process of analysis of tumor stage in GC, and for treatment of GC, the microenvironment of tumor cells plays a vital role [6]. The microenvironment characteristics regulating the development of stage IV GC patients have not been extensively explored
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