Profiles of PD-1, PD-L1, PD-L2 in Gastric Cancer and Their Relation with Mutation, Immune Infiltration, and Survival

BACKGROUND: Although multiple types of cancers demonstrated favorable outcome after immunotherapy of PD-1/PD-L1 blockade, the specific regulatory mechanism of PD genes in gastric cancer (GC) remains largely unknown. MATERIALS AND METHODS: Expression of RNA, copy number variants, and clinical parameters of GC individuals from TCGA were analyzed. Coexpressed genes for PD-1, PD-L1, and PD-L2 were selected by correlation analysis and confirmed by STRING. Gene Ontology and KEGG pathway analyses were performed by clusterProfiler. The influence of PD-1/PD-L1/PD-L2 on immune cell infiltration was investigated by MCP-counter. RESULTS: PD-L2 demonstrated significant relation with clinical stage of GC (P = 0.043). Survival analysis showed that PD-1 expression was correlated with better prognosis of GC patients (HR = 0.70, P = 0.031), but PD-L2 expression was related with worse survival (HR = 1.42, P = 0.032). Mutation of PIK3CA could alter the level of PD-1, PD-L1, and PD-L2 (P < 0.001), and TP53 mutation demonstrated significant correlation with PD-L1 (P = 0.015) and PD-L2 (P = 0.014) expression. Enrichment analysis of PD-1/PD-L1/PD-L2 coexpressed genes indicated a biological process of mononuclear cell proliferation, leukocyte cell-cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1 and Th2, cell differentiation of Th17, and hematopoietic cell landscape. As for immune infiltration analysis, PD-1 was mainly related with cytotoxic lymphocytes and endothelial cells; PD-L1 were associated with monocytic lineage; PD-L2 showed significant correlation with myeloid dendritic cells. CONCLUSION: PD-1 expression showed association with better prognosis of GC, and PD-L2 expression was related with worse survival. Mutations of PIK3CA and TP53 significantly correlated with PD-1/PD-L1/PD-L2 axis. PD-1/PD-L1/PD-L2 coexpressed genes demonstrated enrichment in mononuclear cell proliferation, leukocyte cell-cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1, Th2, and Th17.