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

ABSTRACT: Twenty percent of follicular lymphoma (FL) patients relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive feature are unknown. Using a multiomics approach, we show that FL patients with elevated IRF4 expression (IRF4hi) have poor prognosis, 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272006 | GEO | 2025/06/16

REPOSITORIES: GEO

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

Project description: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.

2025-06-27 | GSE290351 | GEO

Array based comparative genomic hybridisation analysis of 1 Mb resolution of 21 follicular lymphomas (FL), 31 transformed diffuse large B-cells lymphomas (DLBCL), 29 de novo DLBCL (10 of GC and 19 non-GC related immunophenotype).

Project description:Follicular lymphoma (FL) is one of the most common types of indolent B-cell lymphoma in Western countries. FL commonly transforms to more aggressive diffuse large B-cell lymphoma (DLBCL) at reported frequencies between 15 - 60%. We have used microarray comparative genomic hybridisation (aCGH) at 1 Mb resolution to study copy number changes in paired tumor samples (primary FL and a subsequent tDLBCL) as well as de novo DLBCL cases to outline genetic mechanisms of transformation from follicular lymphoma to diffuse large B-cell lymphoma. Single hybridization per case. 21 FL, 31 transformed DLBCL, 29 de novo DLBCL (10 GC and 19 non-GC DLBCL). Tumor labelled with Cy5 and reference with Cy3. Mixture of 20 normal male or female genomic DNA was used in sex-mismatched hybridization.

2014-04-18 | E-GEOD-56884 | biostudies-arrayexpress

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Lymphoma-induced regression of high endothelial venules impairs homeostatic lymphocyte trafficking

Project description:Lymphoma growth is facilitated by the well-balanced infrastructure of the microenvironment in lymph nodes (LN). LNs undergo rapid expansion during lymphoma progression, often accompanied by excessive blood vessel growth. Here we report that aggressive lymphoma cause severe high endothelial venule (HEV) regression which impairs lymphocyte recirculation. In this study, we used transferred (i.v.) Eµ-Myc tumor cells as a mouse model of aggressive lymphoma. Blood endothelial cells from tumor bearing and control LNs were isolated by FACS and processed for single-cell RNA sequencing. The results revealed a detrimental mechanisms causing HEV-dedifferentiation during lymphoma growth with potential implications on tumor-targeting immune surveillance and strategies of immune therapy in LNs

2021-10-14 | E-MTAB-10389 | biostudies-arrayexpress

Profiling of the immune microenvironment in FL

Project description:Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from pro-CTSS to active CTSS and increase substrate cleavage, including CD74 which regulates MHC-II-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4+ T-cells in vitro. Tumors with hyperactive CTSS showed increased CD4+ T-cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment. Digital multiplexed gene expression profiling of formalin-fixed and paraffin-embedded biopsy specimens of the validation cohort was performed as previously described (Hellmuth et al., Blood 2018)

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Profiling of the immune microenvironment in FL [PanCancer Immune Profiling]

Project description:Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from pro-CTSS to active CTSS and increase substrate cleavage, including CD74 which regulates MHC-II-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4+ T-cells in vitro. Tumors with hyperactive CTSS showed increased CD4+ T-cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment. Digital multiplexed gene expression profiling of formalin-fixed and paraffin-embedded biopsy specimens of the GLSG2000 cohort was performed as previously described (Hellmuth et al., Blood 2018)

2020-03-18 | GSE147125 | GEO

Follicular lymphoma microenvironment characteristics associated with tumor cell mutations and MHC class II expression

Project description:Follicular lymphoma (FL) is a B-cell lymphoma with a complex tumor microenvironment that is rich in non-malignant immune cells. We applied single-cell RNA-sequencing to characterize the immune microenvironment of FL. This provides a classification framework of the FL microenvironment, their association with FL genotypes and antigen presentation, and informs different potential immunotherapeutic strategies.

2022-05-28 | GSE203610 | GEO

Translocations Activating IRF4 Identify a Subtype of Germinal-Center-Derived B-cell Lymphoma Affecting Predominantly Children and Young Adults

Project description:Background: Germinal center B-cell (GCB) lymphomas are common in children and adults. The prognosis strongly depends on age. Subgroups of GCB-lymphomas are characterized by chromosomal translocations affecting immunoglobulin (IG) loci leading to oncogene deregulation. Methods: Novel IG translocation partners were cloned within the network “Molecular Mechanisms in Malignant Lymphomas” (MMML) by long-distance inverse polymerase chain reaction. Mature aggressive B-cell lymphomas from the MMML as well as pediatric and adult lymphoma trials were analyzed by fluorescence in situ hybridization (FISH) and immunhistochemistry. Data from 438 MMML cases characterized by gene expression profiling were mined. Results: Cloning of unknown IG partners identified a t(6;14)(p25;q32) juxtaposing the IRF4 oncogene with the IGH-locus as novel recurrent aberration in GCB lymphoma. FISH analyses of 427 mature B-cell lymphomas for IRF4 translocations revealed 20 IG/IRF4 positive lymphomas (17 IGH/IRF4, 2 IGL/IRF4, 1 IGΚ/IRF4). IG/IRF4-positive lymphomas were predominantly GCB-type diffuse large B-cell lymphomas (DLBCL) or follicular lymphoma grade 3, shared overexpression of IRF4/MUM1 and BCL6 and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas was different from other subtypes of DLBCL and a classifier for IG/IRF4 positivity containing 27 genes allowed prediction of 3 additional MMML IG/IRF4-positive cases subsequently proven by FISH. IG/IRF4-positivity was associated with a favorable outcome likely due to significant enrichment of IG/IRF4-positive lymphomas in childhood and young adulthood. Conclusions: Our results suggest IRF4 translocations to be primary genetic alterations in a novel molecularly defined subset of GC-derived lymphomas predominantly affecting children. 271 diffuse large B-Cell lymphoma samples were hybridized to HGU133A Affymetrix GeneChips.

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Transcription profiling of human follicular and transformed follicular lymphoma samples revals genome-wide detection of recurring sites of uniparental disomy

Project description:Follicular lymphoma (FL) is the second most common B-cell malignancy representing one quarter of Non-Hodgkin's Lymphomas. Although the disease has a relatively long median survival, the illness follows a fluctuating course of progression punctuated by remissions of variable duration. For as many as half of patients, transformation to a more aggressive lymphoma (t-FL) may occur; this event is often associated with a particularly poor response to treatment. SNP analysis has revealed the presence of large regions of homozygosity in the absence of copy number change. These events can result in the selection of of daughter cells made homozygous for a pre-existing mutation. We have used SNPs array technology to investigate regions of loss of hetrozygosity in the absence of copy number change in order to establish the contribution of these abnormalities to the evolution of FL and t-FL. Experiment Overall Design: DNA from 26 pairs of follicular and transformed follicular lymphoma samples and 3 cell lines were analysed using Affymetrix 10K SNP arrays. The genotype data of transformed follicular lymphoma samples were compared with the data from the corresponding follicular lymphoma sample.

2008-06-17 | E-GEOD-7425 | biostudies-arrayexpress

Gene expression profiling in follicular lymphoma (FL) samples and paired transformed follicular lymphoma (tFL) (n=6 samples)

Project description:Follicular lymphoma (FL) is the second most common forms of B cell lymphoma that result from the expansion of germinal center (GC) B cells. Here, we aimed to find differential expression of genes between patient samples isolated from indoent FL or transformed and aggressive FL.

2019-12-20 | GSE142334 | GEO

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