MDM2基因扩增或过表达的尿路上皮癌患者的致死性临床结局以及化疗和免疫治疗耐药性

Lethal clinical outcome and chemotherapy and immunotherapy resistance in patients with urothelial carcinoma with MDM2 amplification or overexpression.

作者信息

Jin Kaifeng, Ding Yawei, Xu Jingtong, Liu Zhaopei, Zeng Han, Su Xiaohe, Zhang Lingkai, Sun Jiaxing, Wu Yuzhen, Liu Hailong, Chang Yuan, Zhu Yu, Wang Zewei, Xu Le, Zhang Weijuan, Xu Jiejie

机构信息

Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.

出版信息

J Immunother Cancer. 2025 Jan 6;13(1):e010964. doi: 10.1136/jitc-2024-010964.

DOI:10.1136/jitc-2024-010964

PMID:39762080

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11749520/

Abstract

BACKGROUND

The E3 ubiquitin ligase murine double minute 2 (MDM2) binds the p53 transcriptional activation domain and acts as a potent inhibitor of pathway, one of the three most crucial oncogenic pathways in urothelial carcinoma (UC). However, the clinical significance and impact on tumor immune contexture of amplification in UC remain unclear.

METHODS

This study analyzed 240 patients with UC with matched clinical annotations from two local cohorts (ZSHS cohort and FUSCC cohort). We assessed the correlation between status and clinical outcomes, therapeutic efficacy, and immunological characteristics by immunohistochemical analysis and targeted sequencing. Additionally, 2264 UC samples from five independent external cohorts, with genomic, transcriptomic, and clinical data, were used for validation.

RESULTS

amplification ( ) or protein overexpression (MDM2) was associated with inferior overall survival (ZSHS cohort, Log-rank p<0.001; FUSCC cohort, Log-rank p=0.030) and reduced response to platinum-based chemotherapy (ZSHS cohort, Log-rank p<0.001) as well as anti-PD-1/PD-L1 immunotherapy (FUSCC cohort, Log-rank p=0.016) in patients with UC, irrespective of /p53 status. amplification or overexpression was further linked to high-grade UC tumors with dedifferentiated morphology. In addition, UC with amplification or overexpression was associated with an immuno-evasive contexture characterized by lower proportion of tertiary lymphoid structure infiltration, lower abundance of CD8 T cells, IFN-γ cells, GZMB cells, and decreased expression of immune checkpoint molecules including programmed death-ligand 1 (PD-L1), programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).

CONCLUSIONS

amplification or overexpression defines a lethal subset of patients with UC with inferior prognosis and resistance to both platinum-based chemotherapy and immunotherapy irrespective of /p53 status. These tumors are characterized by dedifferentiated morphology and an immunosuppressive microenvironment. Accurate assessment of status can improve risk stratification and enable personalized genomics-guided treatment for patients with UC.

摘要

背景

E3泛素连接酶小鼠双微体2（MDM2）与p53转录激活域结合，作为尿路上皮癌（UC）中三个最关键的致癌途径之一的有力抑制剂。然而，UC中MDM2扩增的临床意义及其对肿瘤免疫微环境的影响仍不清楚。

方法

本研究分析了来自两个本地队列（ZSHS队列和FUSCC队列）的240例具有匹配临床注释的UC患者。我们通过免疫组织化学分析和靶向测序评估了MDM2状态与临床结局、治疗疗效和免疫特征之间的相关性。此外，来自五个独立外部队列的2264份UC样本，具有基因组、转录组和临床数据，用于验证。

结果

MDM2扩增（MDM2amp）或蛋白过表达（MDM2）与UC患者较差的总生存期相关（ZSHS队列，对数秩检验p<0.001；FUSCC队列，对数秩检验p=0.030），对铂类化疗的反应降低（ZSHS队列，对数秩检验p<0.001）以及对PD-1/PD-L1免疫治疗的反应降低（FUSCC队列，对数秩检验p=0.016），无论MDM2/p53状态如何。MDM2扩增或过表达进一步与形态学去分化的高级别UC肿瘤相关。此外，MDM2扩增或过表达的UC与免疫逃逸微环境相关，其特征为三级淋巴结构浸润比例较低、CD8 T细胞、IFN-γ细胞、GZMB细胞丰度较低，以及包括程序性死亡配体1（PD-L1）、程序性死亡1（PD-1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）在内的免疫检查点分子表达降低。