AUTHOR=Tao Yuting , Li Xia , Zhang Yushan , He Liangyu , Lu Qinchen , Wang Yaobang , Pan Lixin , Wang Zhenxing , Feng Chao , Xie Yuanliang , Lai Zhiyong , Li Tianyu , Tang Zhong , Wang Qiuyan , Wang Xi 

TITLE=TP53-related signature for predicting prognosis and tumor microenvironment characteristics in bladder cancer: A multi-omics study

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.1057302

DOI=10.3389/fgene.2022.1057302

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> The tumor suppressor gene <italic>TP53</italic> is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of <italic>TP53</italic> mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of <italic>TP53</italic> mutation in regulating the tumor microenvironment (TME), elucidate the effects of <italic>TP53</italic> activity on BLCA prognosis and immunotherapy response.</p><p><bold>Methods:</bold> A <italic>TP53</italic>-related signature based on <italic>TP53</italic>-induced and <italic>TP53</italic>-repressed genes was used to construct a <italic>TP53</italic> activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low <italic>TP53</italic> score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low <italic>TP53</italic> activity scores. Finally, the receptor–ligand interactions between immune cells and tumor epithelial cells harboring distinct <italic>TP53</italic> activity were analyzed by single-cell RNA-sequencing.</p><p><bold>Results:</bold> The <italic>TP53</italic> activity-related gene signature differentiated well between <italic>TP53</italic> functional retention and inactivation in BLCA. BLCA patients with low <italic>TP53</italic> scores had worse survival prognosis, more <italic>TP53</italic> mutations, higher grade, and stronger lymph node metastasis than those with high <italic>TP53</italic> scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low <italic>TP53</italic> scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low <italic>TP53</italic> scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor–ligand pairs.</p><p><bold>Conclusion:</bold> BLCA patients with low <italic>TP53</italic> scores have a worse prognosis and a more immunosuppressive TME. This <italic>TP53</italic> activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA.</p>