TP53 Mutations Promote Immunogenic Activity in Breast Cancer

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. TP53 mutations were often associated with worse clinical outcomes in BC whose triple-negative subtype has a high TP53 mutation rate (approximately 80%). To explore a potentially promising therapeutic option for the TP53-mutated BC subtype, we studied the association between TP53 mutations 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 between TP53-mutated and TP53-wildtype BCs based on two large-scale BC multiomics datasets. Moreover, we explored the molecular cues 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.

Results: Bioinformatics analysis showed that almost all analyzed immune signatures showed significantly higher enrichment levels in TP53-mutated BCs than in TP53-wildtype BCs. Moreover, in vitro experiments confirmed that mutant p53 could increase BC immunogenicity. Both computational and experimental results demonstrated 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. Furthermore, we found that elevated immune activity was likely associated with a better survival prognosis in TP53-mutated BCs, but not necessarily in TP53-wildtype BCs.

Conclusions: TP53 mutations may promote immunogenic activity in BC, suggesting that the TP53 mutation status could be a useful biomarker for stratifying BC patients responsive to immunotherapy.