IRF4 promotes immune evasion and shapes the tumor microenvironment in Follicular Lymphoma.

IF 11.5 Q1 HEMATOLOGY

Blood Cancer Discovery Pub Date : 2025-07-16 DOI:10.1158/2643-3230.BCD-24-0223

Surendra Dasari, Kerstin Wenzl, Geoffrey M Nelson, Emmanuel Contreras Guzman, Zhiquan Wang, Loic Chartier, Zhi-Zhang Yang, Jose C Villasboas, Joshua Olson, Prithviraj Mukherjee, Vaishali Bhardwaj, Xinyi Tang, Brianna J Negaard, Johannes L Zakrzewski, Rebecca L King, Sarah Huet, Bruno Tesson, Matthew J Maurer, Franck Morschhauser, Grzegorz S Nowakowski, Karen L Adelman, Harinder Singh, Laura Pasqualucci, Mark Shlomchik, Anne J Novak, Stephen M Ansell, Patrizia Mondello

{"title":"IRF4 promotes immune evasion and shapes the tumor microenvironment in Follicular Lymphoma.","authors":"Surendra Dasari, Kerstin Wenzl, Geoffrey M Nelson, Emmanuel Contreras Guzman, Zhiquan Wang, Loic Chartier, Zhi-Zhang Yang, Jose C Villasboas, Joshua Olson, Prithviraj Mukherjee, Vaishali Bhardwaj, Xinyi Tang, Brianna J Negaard, Johannes L Zakrzewski, Rebecca L King, Sarah Huet, Bruno Tesson, Matthew J Maurer, Franck Morschhauser, Grzegorz S Nowakowski, Karen L Adelman, Harinder Singh, Laura Pasqualucci, Mark Shlomchik, Anne J Novak, Stephen M Ansell, Patrizia Mondello","doi":"10.1158/2643-3230.BCD-24-0223","DOIUrl":null,"url":null,"abstract":"<p><p>Twenty percent of follicular lymphoma (FL) patients relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multi-omics approach, we show that FL patients with elevated IRF4 expression (IRF4hi) have increased transformation risk, dysregulated immune signaling, and a suppressive tumor microenvironment. Loss- and gain-of-function experiments in IRF4hi lymphoma cells, along with chromatin profiling, demonstrate that IRF4 impairs their interaction with T cells by repressing antigen presentation and co-receptor gene modules, while promoting the expression of cytokines that antagonize TFH and Treg functions. Additionally, IRF4 rewires tumor metabolism which restricts glucose availability to immune cells. Silencing of IRF4 inhibits tumor cell growth and restores immune surveillance mechanisms, thus representing a promising target for therapy. Our data suggest that IRF4hi lymphoma cells co-opt a developmental mechanism used to exit the germinal center response in promoting a more aggressive cancer via engagement of multiple immune-evasive mechanisms.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5000,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Cancer Discovery","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1158/2643-3230.BCD-24-0223","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Twenty percent of follicular lymphoma (FL) patients relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multi-omics approach, we show that FL patients with elevated IRF4 expression (IRF4hi) have increased transformation risk, dysregulated immune signaling, and a suppressive tumor microenvironment. Loss- and gain-of-function experiments in IRF4hi lymphoma cells, along with chromatin profiling, demonstrate that IRF4 impairs their interaction with T cells by repressing antigen presentation and co-receptor gene modules, while promoting the expression of cytokines that antagonize TFH and Treg functions. Additionally, IRF4 rewires tumor metabolism which restricts glucose availability to immune cells. Silencing of IRF4 inhibits tumor cell growth and restores immune surveillance mechanisms, thus representing a promising target for therapy. Our data suggest that IRF4hi lymphoma cells co-opt a developmental mechanism used to exit the germinal center response in promoting a more aggressive cancer via engagement of multiple immune-evasive mechanisms.

查看原文本刊更多论文

滤泡性淋巴瘤中IRF4促进免疫逃避和塑造肿瘤微环境。

20%的滤泡性淋巴瘤（FL）患者早期复发，预后较差；然而，这种攻击行为背后的分子机制尚不清楚。使用多组学方法，我们发现IRF4表达升高（IRF4hi）的FL患者转化风险增加，免疫信号失调，肿瘤微环境受到抑制。在IRF4hi淋巴瘤细胞中进行的功能缺失和功能获得实验以及染色质谱分析表明，IRF4通过抑制抗原呈递和共受体基因模块来损害它们与T细胞的相互作用，同时促进拮抗TFH和Treg功能的细胞因子的表达。此外，IRF4重新连接肿瘤代谢，限制免疫细胞的葡萄糖可用性。沉默IRF4抑制肿瘤细胞生长并恢复免疫监视机制，因此代表了一个有希望的治疗靶点。我们的数据表明，IRF4hi淋巴瘤细胞通过参与多种免疫逃避机制，参与一种用于退出生发中心反应的发育机制，从而促进更具侵袭性的癌症。

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

Blood Cancer Discovery Multiple-

CiteScore

12.70

自引率

1.80%

发文量

139

期刊介绍： The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.