TP53 mutations promote immunogenic activity in breast cancer

Abstract

AbstractBackgroundAlthough immunotherapy has recently achieved clinical successes in a variety of cancers, thus far there is no any immunotherapeutic strategy for breast cancer (BC). Thus, it is important to discover biomarkers for identifying the BC patients responsive to immunotherapy. TP53 mutations were often associated with worse clinical outcome in BC, of which the triple-negative BC (TNBC) has a high TP53 mutation rate (approximately 80%). TNBC is high-risk due to its high invasiveness, and lack of targeted therapy. To explore a potentially promising therapeutic option for the TP53-mutated BC subtype, we studied the associations between TP53 mutations and immunogenic activity in BC.MethodsWe compared enrichment levels of 26 immune gene-sets that indicated activities of diverse immune cells, functions, and pathways between TP53-mutated and TP53-wildtype BCs based on two large-scale BC multi-omics data. Moreover, we explored the molecular cues that were associated with the differences in immunogenic activity between TP53-mutated and TP53-wildtype BCs. Furthermore, we performed experimental validation of the findings from bioinformatics analysis.ResultsWe found that almost all analyzed immune gene-sets had significantly higher enrichment levels in TP53-mutated BCs compared to TP53-wildtype BCs. Moreover, our experiments confirmed that mutant p53 could increase BC immunogenicity. Furthermore, our computational and experimental results showed that TP53 mutations could promote BC immunogenicity via regulation of the p53-mediated pathways including cell cycle, apoptosis, Wnt, Jak-STAT, NOD-like receptor, and glycolysis. Interestingly, we found that elevated immune activities were likely to be associated with better survival prognosis in TP53-mutated BCs, but not necessarily in TP53-wildtype BCs.ConclusionsTP53 mutations promote immunogenic activity in breast cancer. This finding demonstrates a different effect of p53 dysfunction on tumor immunogenicity from that of previous studies, suggesting that the TP53 mutation status could be a useful biomarker for stratifying BC patients responsive to immunotherapy.