IRF4 Promotes Immune Evasion and Shapes the Tumor Microenvironment in Follicular Lymphoma
Year: 2025
Type: article
Abstract: Twenty percent of patients with follicular lymphoma relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multiomic approach, we show that patients with follicular lymphoma 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 T-follicular helper cell and regulatory T-cell functions. Additionally, IRF4 rewires tumor metabolism and 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. SIGNIFICANCE: We show that IRF4 controls immune and metabolic signaling with functional effects on the cross-talk between B and T cells, resulting in a suppressive immune microenvironment when IRF4 is overexpressed in lymphoma. This underscores the importance of IRF4 as a pivotal therapeutic target to restore antitumor immunosurveillance for IRF4-associated lymphomas.
Source: Blood Cancer Discovery
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
Institutions: Mayo Clinic, Harvard University, The Lymphoma Academic Research Organisation, Hôpital Lyon Sud, Hackensack Meridian Health, Hospices Civils de Lyon, Centre International de Recherche en Infectiologie, Centre Hospitalier Universitaire de Lille, University of Pittsburgh, Columbia University
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4412478356