MDMX phosphorylation-dependent p53 downregulation contributes to an immunosuppressive tumor microenvironment

• 来源期刊: 分子细胞生物学报（英文版）
• 年，卷（期）: 2020,（9）
• 所属期刊栏目: Articles
• 页码范围: 713-722
• 页数: 10页
• 语种: 英文
• DOI: 10.1093/jmcb/mjaa038

摘要

A role of tumor-suppressive activity of p53 in the tumor microenvironment (TME) has been implicated but remains fairly under-studied.To address this knowledge gap,we leveraged our MdmxS314 mice as recipients to investigate how implanted tumor cells incapacitate host p53 creating a conducive TME for tumor progression.We found that tumor cell-associated stress induced p53 downregulation in peritumor cells via an MDMX-Ser314 phosphorylation-dependent manner.As a result,an immunosuppressive TME was developed,as reflected by diminished immune cell infiltration into tumors and compromised macrophage M1 polariza-tion.Remarkably,ablation of MDMX-Ser314 phosphorylation attenuated p53 decline in peritumor cells,which was associated with mitigation of immunosuppression and significant tumor growth delay.Our data collectively uncover a novel role of p53 in regulating the tumor immune microenvironment,suggesting that p53 restoration in the TME can be exploited as a potential strat-egy of anticancer therapy.