CXCR2P1 enhances the response of gastric cancer to PD-1 inhibitors through increasing the immune infiltration of tumors.

Background: Recent years, immunotherapy has emerged as a pivotal approach in cancer treatment. However, the response of gastric cancer to immunotherapy exhibits significant heterogeneity. Therefore, the early identification of gastric cancer patients who are likely to benefit from immunotherapy and the discovery of novel therapeutic targets are of critical importance.

Materials and methods: We collected data from European Nucleotide Archive (ENA) and Gene Expression Omnibus (GEO) databases. In project PRJEB25780, we performed WGCNA analysis and Lasso regression and chose CXCR2P1 for the subsequent analysis. Then, we compared the expression difference of CXCR2P1 among different groups. Kaplan-Meier curve was used to analyze the prognostic value of CXCR2P1, which was validated by project IMvigor210 and GEO datasets. ESTIMATE and CIBERSORT algorithm were used to evaluate the reshaping effect of CXCR2P1 to immune microenvironment of tumor. Differentially expressed genes (DEG) analysis, enrichGO analysis, Gene Set Enrichment Analysis (GSEA) and co-expression analysis were used to explore the cell biological function and signaling pathway involved in CXCR2P1.

Results: WGCNA identified CXCR2P1 as a hub gene significantly associated with immune response to PD-1 inhibitors in gastric cancer. CXCR2P1 expression was elevated in responders and correlated with better prognosis. Functional analysis revealed its role in reshaping the tumor immune microenvironment by promoting immune cell infiltration, including M1 macrophages, activated CD4+ T cells, and follicular helper T cells. CXCR2P1 enhanced antigen presentation via the MHC-II complex, influenced key immune pathways, such as Toll-like receptor signaling and T-cell activation, which led to the up-regulation of expression of PD-L1. GSEA showed CXCR2P1 were correlated with microRNAs. Through DEG analysis and expression analysis, MIR215 was identified as a potential direct target of CXCR2P1.

Conclusion: High expression of CXCR2P1 is correlated with better response to PD-1 inhibitor. It reshapes the immune microenvironment by increasing immune infiltration and changing the fraction of immune cells. In tumor immune microenvironment, CXCR2P1 can promote inflammation, enhance antigen presentation and activate the PD-1/PD-L1-related signaling pathway, which might be achieved by CXCR2P1-MIR215 axis.