Expression of EPB41L2 in Cancer-Associated Fibroblasts: Prognostic Implications for Bladder Cancer and Response to Immunotherapy

IF 4.7 3区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Archives of Medical Research Pub Date : 2024-01-01 DOI:10.1016/j.arcmed.2023.102927

Tianqi Wang , Guixin Ding , Xiaoyu Wang , Yuanshan Cui , Xiaohong Ma , Jian Ma , Jitao Wu

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Abstract

Background

Immunotherapy response in patients with bladder cancer (BLCA) treated with immune checkpoint inhibitors (ICIs) is variable. The accurate evaluation of immunotherapy efficacy may be facilitated by the tumor microenvironment (TME). Erythrocyte membrane protein band 4.1 like 2 (EPB41L2), a cytoskeletal protein with a regulatory role in the TME was intensively investigated to determine its biological characterization, clinical relevance, and predictive value for immunotherapy in BLCA.

Methods

Comprehensive bioinformatics and statistical analyses were conducted to examine gene expression profile, TME components, immune contexture, molecular features, and prediction of immunotherapy response. Immunohistochemistry (IHC) validated the results of the bioinformatics analysis. Association between immune checkpoint genes (ICGs) and EPB41L2-based risk stratification was validated in the IMvigor210 cohort, and their association with ICI response was assessed.

Results

EPB41L2 mRNA levels were decreased in BLCA compared to normal tissue. IHC showed reduced EPB41L2 staining intensity in early BLCA tissue. Nevertheless, elevated EPB41L2 expression was observed in cancer-associated fibroblasts (CAFs) with higher histological grade and pathological stage. High EPB41L2 expression served as a poor prognostic factor for BLCA. Single-cell RNA-seq and further analyses revealed that EPB41L2 was mainly expressed in CAFs and promoted TME remodeling. EPB41L2^low/ICGs^high patients showed greater benefit from immunotherapy. Gene mutation analysis revealed a close relationship between EPB41L2 and the frequency of oncogenic mutations, including TP53 and FGFR3.

Conclusion

Comprehensive analysis and IHC confirmed the upregulation of EPB41L2 in BLCA CAFs and its association with TME remodeling. EPB41L2 and ICG expression were identified as combinatorial biomarkers to predict the response to immunotherapy.

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EPB41L2在癌症相关成纤维细胞中的表达：膀胱癌的预后意义及对免疫疗法的反应

背景接受免疫检查点抑制剂（ICIs）治疗的膀胱癌（BLCA）患者的免疫治疗反应各不相同。肿瘤微环境（TME）有助于准确评估免疫疗法的疗效。研究人员对红细胞膜蛋白带4.1 like 2（EPB41L2）这一在TME中起调控作用的细胞骨架蛋白进行了深入研究，以确定其生物学特征、临床相关性以及对BLCA免疫治疗的预测价值。研究人员进行了全面的生物信息学和统计学分析，以研究基因表达谱、TME成分、免疫环境、分子特征以及免疫治疗反应预测。免疫组化（IHC）验证了生物信息学分析的结果。在IMvigor210队列中验证了免疫检查点基因（ICGs）与基于EPB41L2的风险分层之间的关联，并评估了它们与ICI反应的关联。IHC显示，早期BLCA组织中EPB41L2染色强度降低。然而，在组织学分级和病理分期较高的癌相关成纤维细胞（CAFs）中观察到 EPB41L2 表达升高。EPB41L2的高表达是BLCA的不良预后因素。单细胞RNA-seq和进一步分析表明，EPB41L2主要在CAFs中表达，并促进TME重塑。EPB41L2低/ICG高的患者从免疫疗法中获益更大。基因突变分析表明，EPB41L2与TP53和FGFR3等致癌基因突变的频率有密切关系。EPB41L2和ICG的表达被确定为预测免疫疗法反应的组合生物标记物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Archives of Medical Research 医学-医学：研究与实验

CiteScore

12.50

自引率

0.00%

发文量

审稿时长

28 days

期刊介绍： Archives of Medical Research serves as a platform for publishing original peer-reviewed medical research, aiming to bridge gaps created by medical specialization. The journal covers three main categories - biomedical, clinical, and epidemiological contributions, along with review articles and preliminary communications. With an international scope, it presents the study of diseases from diverse perspectives, offering the medical community original investigations ranging from molecular biology to clinical epidemiology in a single publication.