IRF4 promotes immune-evasion and shapes the Tumor Microenvironment in Follicular Lymphoma
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PROVIDER: PRJNA1227527 | ENA |
REPOSITORIES: ENA
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Project description:IRF4 promotes immune-evasion and shapes the Tumor Microenvironment in Follicular Lymphoma
| PRJNA1134612 | ENA
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
Project description: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.
2025-06-16 | GSE272006 | GEO
Project description:Sequencing Follicular Lymphoma
| PRJNA348784 | ENA
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.
2011-06-24 | E-GEOD-22470 | biostudies-arrayexpress
Project description:Tumor cells can induce their own advantageous microenvironment. Here, we describe aberrant cathepsin S (CTSS) activity to modulate T-cell activation in follicular lymphoma (FL). In donor-derived FLs following bone marrow transplantation, we identified independent acquisition of CTSS mutations at Y132 in the donor´s and recipient's tumors. In a larger cohort, 6% of FL (20/312) harbored CTSS mutations, mostly Y132D, another 14% had CTSS amplification (40/280). Y132D leads to accelerated conversion from pro-CTSS to active CTSS and increased substrate cleavage, including CD74, which regulates MHC-II restricted antigen-presentation. In co-culture experiments, CTSS mutant lymphoma cells induced increased antigen-specific CD4+ T-cell activation. Moreover, antigen-processing was the top upregulated pathway in CTSS mutant primary FL biopsies. Thus, aberrant CTSS activity is a promising target in lymphoma.
2021-01-07 | PXD014612 | Pride
Project description:The hallmark of follicular lymphoma (FL) is the t(14;18) chromosomal translocation. However, constitutive expression of anti-apoptotic Bcl-2 alone is insufficient for lymphomagenesis and subsequent molecular hits are required. We explored the role of microRNA (miRNA or miR) in the biology of FL by generating miRNA profiles of enriched sorted grade 1 and 2 FL tumor cells derived from 18 patients compared with enriched germinal center B-cells derived from seven follicular hyperplasia (FH). Expression levels of 851 human miRs were assayed and 133 miRs were significantly differentially expressed in FL tumor cells. The expression of 44 miRs in three major groups generated a unique FL signature. MiRs in group 1 were increased in FL (miR-193-5p, -193b*, -345, -513b, -574-3p, -584, -663, -1287, -1295, and -1471). Group 2 was increased in the majority of FL cases but showed lower levels of expression in a subset of FL (let-7a, let-7f, miR-7-1*, -9, -9*, -20a, -20b, -30b, -96, -98, -194, -195, -221*, -374a, -451, -454, -502-3p, -532-3p, -574-3p, -664*, -1274a, -1274b, and -1260). MiR group 3 was decreased in FL (miR-17*, -30a, 33a, 106a*, -141, 202, -205, -222, 301b, -431*, and -570). Two patterns within FL were detected, largely due to the variable expression of group 2 miRs. The pattern with higher expression of group 2 miRs was associated with complete response to chemotherapy. Gene expression analysis of 199 genes related to lymphoma and tumor development performed in tandem indicated differential expression of 47 genes in FL including increased expression of AKT-1, PRKCE, IL4R, DROSHA, and MAPK1; and decreased expression of CHEK1, RAD51, CDKN1A, SOCS2, KLF4, BLIMP1 and IRF4. Functional studies provide evidence that miR-20a and -20b target CDKN1A/p21, miR-194 targets SOCS2, and miR-301b targets MAPK1 in FL, affecting cell proliferation and potentially contributing to lymphomagenesis. These findings suggest a role for aberrant miRNA expression in the biology of FL with prognostic and mechanistic implications. miRNA profiling was performed using Agilent miRNA array platform with RNAs isolated from sorted follicular lymphoma B cells and follicular hyperplasia B cells.
2012-05-02 | E-GEOD-28090 | biostudies-arrayexpress
Project description:The microenvironment of human follicular lymphoma (FL), an incurable B cell non-Hodgkin's lymphoma, is thought to play a major role in its pathogenesis and course. Microenvironmental cells of likely importance include follicular Th cells (TFH) and regulatory T cells (Tregs), and understanding their interactions with FL tumor cells is necessary to develop novel therapeutic strategies. We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. IL-4 alone induces only CCL17 but enhances stimulation by CD40L of both CCL17 and CCL22. Consistent with our in vitro results, mRNA transcripts of IL-4 correlated with CCL17, but not CCL22, in gene expression profiling studies of FL biopsies, whereas CD40L correlated with both CCL17 and CCL22. Tumor supernatants induced preferential migration of Tregs and IL-4-producing T cells rather than IFN-?-producing T cells, and Abs to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4-producing T cells, which, in turn, may stimulate more chemokine production in a feed-forward cycle. Thus, TFH appear to play a major role in generating an immunosuppressive tumor microenvironment that promotes immune escape and tumor survival and growth. Our results provide novel insights into the cross talk among TFH, tumor cells, and Tregs in FL, and offer potential targets for development of therapeutic strategies to overcome immune evasion.
| S-EPMC3680117 | biostudies-literature
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.
2011-06-24 | GSE22470 | GEO
Project description:We used microarrays to detail gene expression profile of several follicular lymphoma patient samples with different grades
2012-04-30 | GSE37088 | GEO