IRF4 promotes immune-evasion and shapes the Tumor Microenvironment in Follicular Lymphoma

Twenty percent of follicular lymphoma (FL) patients relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multiomics 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. Fresh-frozen lymph node samples from 21 FL patients (n=10 IRF4hi, n=11 IRF4lo) were used to single cell RNA-seq/scBCR-seq *************************************************************** Raw files for human/patient samples were not submitted to GEO due to concerns about submitting personally identifiable sequence data for open access. ***************************************************************

20%的滤泡性淋巴瘤（follicular lymphoma, FL）患者会早期复发且预后不良，但其侵袭性表型背后的分子机制尚未明确。本研究采用多组学方法，发现干扰素调节因子4（Interferon Regulatory Factor 4, IRF4）高表达的FL患者（IRF4hi）具有更高的组织学转化风险、免疫信号通路失调特征以及免疫抑制型肿瘤微环境。对IRF4hi淋巴瘤细胞开展功能缺失与功能获得实验，并结合染色质图谱分析（chromatin profiling），结果显示IRF4可通过抑制抗原递呈与共受体基因模块，削弱肿瘤细胞与T细胞的相互作用，同时促进可拮抗滤泡辅助性T细胞（follicular helper T cell, TFH）与调节性T细胞（regulatory T cell, Treg）功能的细胞因子表达。此外，IRF4可重编程肿瘤代谢程序，限制免疫细胞可获得的葡萄糖供应量。沉默IRF4可抑制肿瘤细胞生长并恢复免疫监视功能，因此IRF4是极具潜力的治疗靶点。本研究数据表明，IRF4hi淋巴瘤细胞通过劫持一套用于退出生发中心反应的发育程序，借助多种免疫逃逸途径推动癌症向更具侵袭性的表型进展。本研究纳入21例FL患者的新鲜冷冻淋巴结组织样本（其中IRF4hi组10例，IRF4lo组11例），用于开展单细胞RNA测序（single cell RNA-seq）与单细胞B细胞受体测序（scBCR-seq）。**************************************************************** 鉴于将包含个人可识别信息的测序数据提交至开放获取平台存在隐私风险，本研究未将人类患者样本的原始测序文件上传至基因表达综合数据库（Gene Expression Omnibus, GEO）。****************************************************************