TP53Mutations Promote Immunogenic Activity in Breast Cancer

Abstract

Background. Although immunotherapy has recently achieved clinical successes in a variety of cancers, thus far there is no immunotherapeutic strategy for breast cancer (BC). Thus, it is important to discover biomarkers for identifying BC patients responsive to immunotherapy.TP53mutations were often associated with worse clinical outcomes in BC whose triple-negative subtype has a highTP53mutation rate (approximately 80%). To explore a potentially promising therapeutic option for theTP53-mutated BC subtype, we studied the association betweenTP53mutations and immunogenic activity in BC.Methods. We compared the enrichment levels of 26 immune signatures that indicated activities of diverse immune cells, functions, and pathways betweenTP53-mutated andTP53-wildtype BCs based on two large-scale BC multiomics datasets. Moreover, we explored the molecular cues associated with the differences in immunogenic activity betweenTP53-mutated andTP53-wildtype BCs. Furthermore, we performed experimental validation of the findings from bioinformatics analysis.Results. Bioinformatics analysis showed that almost all analyzed immune signatures showed significantly higher enrichment levels inTP53-mutated BCs than inTP53-wildtype BCs. Moreover,in vitroexperiments confirmed that mutant p53 could increase BC immunogenicity. Both computational and experimental results demonstrated thatTP53mutations could promote BC immunogenicityviaregulation of the p53-mediated pathways including cell cycle, apoptosis, Wnt, Jak-STAT, NOD-like receptor, and glycolysis. Furthermore, we found that elevated immune activity was likely associated with a better survival prognosis inTP53-mutated BCs, but not necessarily inTP53-wildtype BCs.Conclusions.TP53mutations may promote immunogenic activity in BC, suggesting that theTP53mutation status could be a useful biomarker for stratifying BC patients responsive to immunotherapy.