CDKN2A deletion is associated with immune desertification in diffuse pleural mesothelioma.

IF 12.8 1区 医学 Q1 ONCOLOGY
Federica Torricelli, Benedetta Donati, Veronica Manicardi, Mila Gugnoni, Francesca Reggiani, Gloria Manzotti, Pierluigi Di Chiaro, Cristian Ascione, Simonetta Piana, Riccardo Valli, Roberto Piro, Massimiliano Paci, Nicola Facciolongo, Filippo Lococo, Alessia Ciarrocchi
{"title":"CDKN2A deletion is associated with immune desertification in diffuse pleural mesothelioma.","authors":"Federica Torricelli, Benedetta Donati, Veronica Manicardi, Mila Gugnoni, Francesca Reggiani, Gloria Manzotti, Pierluigi Di Chiaro, Cristian Ascione, Simonetta Piana, Riccardo Valli, Roberto Piro, Massimiliano Paci, Nicola Facciolongo, Filippo Lococo, Alessia Ciarrocchi","doi":"10.1186/s13046-025-03522-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Diffuse Pleural Mesothelioma (DPM) is a rare and incurable cancer. Immune checkpoint inhibitors (ICIs) marked some advances but only for a limited fraction of patients. Improving response prediction to ICIs is currently a clinical need in DPM. Deletion of CDKN2A gene, in chr9p21.3, is one of the most frequent alterations in DPM. As in other settings, deletion of CDKN2A locus has been associated with an immunosuppressive phenotype. Here we investigated the consequences of CDKN2A deletion (CDKN2Adel) on the tridimensional organization and function of immune infiltrate in DPM.</p><p><strong>Methods: </strong>A retrospective cohort of 89 DPMs was analyzed and assessed for CDKN2Adel through digital droplet PCR. Immune-profiling was assessed by analyzing 770 immune-related genes by digital profiling. Finally, morphologically resolved, high-dimensional transcriptomic approach was used to reconstruct the spatial architecture of immune-tumor interaction in wild-type and deleted FFPE samples.</p><p><strong>Results: </strong>CDKN2Adel was detected in 41.5% of DPMs and was associated with reduced survival (p = 0.04). Bulk gene expression identified 373 differentially expressed genes, of which 98.6% were downregulated in CDKN2Adel samples. These genes were enriched in several immune categories, suggesting significant immune deprivation in deleted tumors. Deconvolution analysis confirmed a major depletion of infiltrating immune cells including effector populations. Spatial transcriptomics revealed that this immunosuppressive phenotype was different according to histotype and prominent in the sarcomatoid lesions.</p><p><strong>Conclusion: </strong>These data demonstrated that CDKN2Adel deeply affects the spatial organization of immune microenvironment by depleting immune-signaling and reducing or preventing immune infiltration, supporting the potential implementation of this alteration as ICIs predictive biomarker in DPM.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"256"},"PeriodicalIF":12.8000,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12392524/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental & Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13046-025-03522-4","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction: Diffuse Pleural Mesothelioma (DPM) is a rare and incurable cancer. Immune checkpoint inhibitors (ICIs) marked some advances but only for a limited fraction of patients. Improving response prediction to ICIs is currently a clinical need in DPM. Deletion of CDKN2A gene, in chr9p21.3, is one of the most frequent alterations in DPM. As in other settings, deletion of CDKN2A locus has been associated with an immunosuppressive phenotype. Here we investigated the consequences of CDKN2A deletion (CDKN2Adel) on the tridimensional organization and function of immune infiltrate in DPM.

Methods: A retrospective cohort of 89 DPMs was analyzed and assessed for CDKN2Adel through digital droplet PCR. Immune-profiling was assessed by analyzing 770 immune-related genes by digital profiling. Finally, morphologically resolved, high-dimensional transcriptomic approach was used to reconstruct the spatial architecture of immune-tumor interaction in wild-type and deleted FFPE samples.

Results: CDKN2Adel was detected in 41.5% of DPMs and was associated with reduced survival (p = 0.04). Bulk gene expression identified 373 differentially expressed genes, of which 98.6% were downregulated in CDKN2Adel samples. These genes were enriched in several immune categories, suggesting significant immune deprivation in deleted tumors. Deconvolution analysis confirmed a major depletion of infiltrating immune cells including effector populations. Spatial transcriptomics revealed that this immunosuppressive phenotype was different according to histotype and prominent in the sarcomatoid lesions.

Conclusion: These data demonstrated that CDKN2Adel deeply affects the spatial organization of immune microenvironment by depleting immune-signaling and reducing or preventing immune infiltration, supporting the potential implementation of this alteration as ICIs predictive biomarker in DPM.

CDKN2A缺失与弥漫性胸膜间皮瘤免疫沙化相关
弥漫性胸膜间皮瘤(DPM)是一种罕见且无法治愈的癌症。免疫检查点抑制剂(ICIs)标志着一些进展,但仅适用于有限部分患者。改善对ICIs的反应预测是目前DPM的临床需要。在chr9p21.3中,CDKN2A基因的缺失是DPM中最常见的改变之一。与其他情况一样,CDKN2A基因座的缺失与免疫抑制表型有关。在这里,我们研究了CDKN2A缺失(CDKN2Adel)对DPM中免疫浸润三维组织和功能的影响。方法:通过数字液滴PCR对89例dpm进行回顾性分析和CDKN2Adel检测。通过数字谱分析770个免疫相关基因来评估免疫谱。最后,采用形态学解析的高维转录组学方法重建野生型和缺失FFPE样本中免疫-肿瘤相互作用的空间结构。结果:41.5%的dpm中检测到CDKN2Adel,并与生存率降低相关(p = 0.04)。大量基因表达鉴定出373个差异表达基因,其中98.6%在CDKN2Adel样本中下调。这些基因在几个免疫类别中富集,表明在缺失的肿瘤中存在显著的免疫剥夺。反褶积分析证实了浸润性免疫细胞包括效应细胞群的大量耗竭。空间转录组学显示,这种免疫抑制表型根据组织型不同而不同,在肉瘤样病变中表现突出。结论:这些数据表明CDKN2Adel通过消耗免疫信号和减少或阻止免疫浸润而深刻影响免疫微环境的空间组织,支持这种改变作为ICIs在DPM中的预测生物标志物的潜在实现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信