p53 and PD-1/PD-L1 expression contribute to disease progression and are correlated to immune infiltrates in urothelial carcinoma

The relevance and clinical significance of p53 and PD-1/PD-L1 in urothelial carcinoma (UC) are still unknown. This study was to explore the expression, clinical significance, and correlation of p53, PD-1/PD-L1, as well as their associations with immune cells, immune checkpoints and immunotherapy in UC. The expression of p53 and PD-1/PD-L1 were analyzed by the tumor immune estimation resource (TIMER), SangerBox, Gene Expression Profiling Interactive Analysis (GEPIA) databases and immunohistochemistry. The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) and Kaplan-Meier plotter databases were used to examine the clinical and prognostic value of p53 and PD-1/PD-L1 in bladder cancer (BLCA). Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to analyze the potential mechanisms between p53, PD-1/PD-L1, and their co-expression genes and proteins identified through the GeneMANIA, STRING databases, and competitive endogenous RNA (ceRNA) network. The TIMER, GEPIA2, and An integrated repository portal for tumor-immune system interactions (TISIDB) databases were used to analyze the correlation of p53 and PD-1/PD-L1 expression with immune cell infiltration and immune cell gene markers in BLCA. Finally, the association between p53, PD-1/PD-L1 expression and immunotherapy checkpoint inhibitor (ICB), tumor mutation burden (TMB), tumour immune dysfunction and exclusion (TIDE) scores, and immunotherapy in TCGA-BLCA data was analyzed using the "Limma" package. Overall, p53 and PD-L1 expression were found to be significantly different between UC tissues and adjacent normal tissues, whereas no significant difference in PD-1 expression was observed. Pan-cancer survival analysis showed that p53, PD-1/PD-L1 were significantly associated with the prognosis of a variety of pan-cancers, including overall survival (OS) and relapse-free survival (RFS). However, further analysis also confirmed that only low PD-1 expression was associated with poorer OS and RFS in BLCA. In addition, p53 and PD-1/PD-L1 expression are closely related to adverse clinicopathological features. The correlation analysis between p53 and PD-1/PD-L1 showed a significant negative correlation between p53 and PD-1, while PD-1 was significantly positively correlated with PD-L1. Notably, p53 and PD-1/PD-L1 were found to be involved in the regulation of immune responses in GeneMANIA, STRING, ceRNA network, and functional enrichment analysis. Further analysis indicated that p53 and PD-1/PD-L1 were associated with specific immune cells and immune cell gene markers, which may partially affect UC prognosis due to the level of immune cell infiltration. Meanwhile, the correlation analysis of p53, PD-1/PD-L1 with ICB, TMB, TIDE scores and immunotherapy revealed that p53 had a better immunotherapeutic effect in PD-1 negative BLCA patients; Whereas, high PD-1/PD-L1 expression had a better immunotherapeutic effect regardless of CTLA4 and/or PD-1 positivity. As an immune gene or protein associated with PD-1/PD-L1, p53 is significantly negatively correlated with PD-1. High expression of p53 may inhibit PD-1 expression, further inhibiting the PD-1/PD-L1 axis to reduce immunosuppressive status. In addition, p53 may also block the formation of PD-1/PD-L1 resistance by inhibiting the polarization of TAMs and M2 macrophages. This work demonstrates the important role of p53 in PD-1/PD-L1 axis-based immunotherapy for UC patients, and p53 is expected to become a key target for breaking through the current status of immunotherapy.