Immunogenomics Analysis Reveals That TP53 Mutations Inhibit Tumor Immunity in Gastric Cancer

Although immunotherapy continues to demonstrate efficacy in a variety of refractory cancers, currently, no any immunotherapeutic strategy is clinically used for gastric cancer (GC) except its microsatellite instable subtype. Thus, it is important to identify molecular biomarkers for predicting the responders to GC immunotherapy. TP53 mutations frequently occur in GC and are associated with unfavorable clinical outcomes in GC. We performed a comprehensive characterization of the associations between TP53 mutations and immune activities in GC based on two large-scale GC cancer genomics data. We compared expression and enrichment levels of 787 immune-related genes and 23 immune gene-sets among TP53-mutated GCs, TP53-wildtype GCs, and normal tissue, and explored the correlations between p53-mediated pathways and immune activities in GC. Strikingly, almost all analyzed immune gene-sets were significantly downregulated in enrichment levels in TP53-mutated GCs compared to TP53-wildtype GCs. These less active immune pathways and cell types in TP53-mutated GCs included 15 immune cell types and function, tumor-infiltrating lymphocytes, regulatory T cells, immune checkpoint, cytokine and cytokine receptor, human leukocyte antigen, pro-inflammatory, and parainflammation. Moreover, we identified a number of p53-mediated pathways and proteins that were significantly associated with immune activities in GC. Furthermore, we demonstrated that the TP53 mutation itself could result in the depressed immune activities in GC and other cancer types. We revealed that chromosomal instability was an important mechanism for the depressed tumor immunity in TP53-mutated cancers. Finally, we showed that immune cell infiltration and immune activities were likely positively associated with survival prognosis in GC. Our findings suggest that p53 may play an important role in activating tumor immunity in GC and other cancer types and that the TP53 mutation status could be useful in stratifying cancer patients responsive to a certain immunotherapy.