TP53 Mutations Promote Immunogenic Activity in Breast Cancer.

Zhixian Liu,Yingsheng Gao,Zehang Jiang,Xiaosheng Wang,Lirui Wang,Cai Chen

doi:10.1155/2019/5952836

Zhixian Liu, Yingsheng Gao + Show 4 more

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https://doi.org/10.1155/2019/5952836

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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. 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.

Highlights

The tumor suppressor p53 plays an important role in the regulation of cell-cycle, apoptosis, DNA repair, cellular senescence, and autophagy [1]
On the basis of the the Cancer Genome Atlas (TCGA) breast cancer (BC) pathological slides data, we found that TP -mutated BCs had markedly higher percentages of lymphocyte infiltration compared to TP -wildtype BCs (Mann-Whitney U test, P=0.01) (Figure 1(c))
These data indicate that TP mutations are associated with elevated immune activity in BC

Summary

Introduction

The tumor suppressor p53 plays an important role in the regulation of cell-cycle, apoptosis, DNA repair, cellular senescence, and autophagy [1]. Some molecular biomarkers associated with cancer immunotherapy response have been identified, e.g., tumor mutation burden (TMB) [12], neoantigens [13], dMMR [14], and PD-L1 expression [15]. Few studies have correlated the TP mutation status with cancer immunotherapy response, a recent clinical trial (phase II) data showed that patients with mutated-p53 metastatic breast cancer had better overall survival (OS) when treated with the immunooncology viral agent REOLYSIN5 in combination with paclitaxel [16]. In vitro experiments confirmed that mutant p53 could increase BC immunogenicity Both computational and experimental results demonstrated that TP mutations could promote BC immunogenicity via regulation of the p53-mediated pathways including cell cycle, apoptosis, Wnt, Jak-STAT, NOD-like receptor, and glycolysis. TP mutations may promote immunogenic activity in BC, suggesting that the TP mutation status could be a useful biomarker for stratifying BC patients responsive to immunotherapy

Methods

Results

Conclusion