Activated CD4 T cells/Tregs derived immune-metabolism signature provide precise prognosis assessment for gastric cancer and beneficial for treatment option.

Background: The prognostic significance of the ratio of activated CD4 T cells to Tregs infiltrating tumor tissues in gastric cancer (GC) remains unknown. Materials and methods: For the quantification of infiltration of immune cells, the ssGSEA algorithm, which is a single sample gene set enrichment analysis, was utilized. Group A was defined as having activated CD4 T cells/Tregs >1, while group B was defined as having activated CD4 T cells/Tregs <1. To compare the overall survival (OS) of the two groups, the Kaplan-Meier survival analysis was employed. The R package 'limma' was used to identify the immune and metabolism related genes that were expressed differentially between the two groups, with a false discovery rate (FDR) less than 0.05. The risk score (RS) was constructed by combining univariate Cox regression analysis, LASSO penalized Cox regression analysis, and multivariate Cox regression analysis. The median RS was used to classify high-risk (HR) and low-risk (LR) groups. Results: A predicted unfavorable outcome of GC was observed when the ratio of activated CD4 T cells to Tregs was less than 1. Our proposed RS was utilized for prognostic risk categorization in ten distinct independent cohorts (TCGA-STAD, n = 371; GSE84437, n = 433; GSE26253, n = 432; GSE13861, n = 65; GSE15459, n = 192; GSE26899, n = 93; GSE26901, n = 109; GSE28541, n = 40; GSE34942, n = 56; GSE62254, n = 300) and exhibited exceptional precision. In terms of tumor microenvironment (TME) and treatment strategies, compared to the LR group, the HR group was characterized by a higher infiltration levels of stromal cells, Tregs, macrophages, Tfh, mast cells, and NK cells, inclined to activated CD4 T cells/Tregs <1, and exhibited insensitivity to immunotherapy and multiple chemotherapy drugs. In relation to the potential molecular mechanism, the excessive activation of oncogenic pathways such as MAPK, hedgehog, WNT, calcium, and TGF-β signaling pathways may accelerate the malignant progression of GC by stimulating angiogenesis, promoting EMT, and altering ECM. Conversely, the overactivation of the P53 pathway is likely to inhibit tumor proliferation by regulating the cell cycle. Conclusion: The immune-metabolism signature associated with the ratio of activated CD4 T cells and Tregs could be used to assess prognosis, TME, and treatment strategies in GC patients.