Coreceptor delivery of paracrine APRIL to Golgic BCMA lowers immunogenicity of B-cell lymphoma
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PROVIDER: PRJNA453495 | ENA |
REPOSITORIES: ENA
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Project description:APRIL is involved in the development of B-cell lymphomas. However, in tumors the source of APRIL is paracrine while one signaling receptor, BCMA, is intracellular, raising the question on how APRIL may signal. In fact, tumor cells internalized APRIL via their surface HSPG. Then, APRIL trafficked into endosomes to finally interact with Golgic BCMA, whose sequence harbors strong identities with sorting nexins. Intracellular APRIL/BCMA interactions activated the canonical NF-kB pathway, and mediated from tumor cells an immunosuppressive response including IL-10 upregulation. Absence of APRIL/BCMA interactions impaired tumor growth in mice, and APRIL internalization by tumor cells correlated with a reduced survival for patients. Taken together, the present study elucidates a fully intracellular signaling pathway, key to B-cell lymphoma development.
2018-04-26 | GSE113643 | GEO
Project description:APRIL (TNFSF13) is a ligand of the TNF superfamily which binds to two receptors, BCMA and TACI. We have found that APRIL and its receptor BCMA are specifically enhanced in hepatocellular carcinoma, as compared to non-cancerous liver tissue. We further identified that HepG2 cells present the same ligand/receptor pattern as human hepatocellular carcinomas. We investigated the role of APRIL in HepG2 gene expression in a time course study. 24 hour serum starved HepG2 cells were treated with 200ng/ml of APRIL and RNA was collected at 0, 2, 6, and 12h. The collected RNA was used for hybridization on commercially available Affymetrix Human Genome U133 Plus 2.0 Arrays
2011-05-20 | E-GEOD-29375 | biostudies-arrayexpress
Project description:APRIL (TNFSF13) is a ligand of the TNF superfamily which binds to two receptors, BCMA and TACI. We have found that APRIL and its receptor BCMA are specifically enhanced in hepatocellular carcinoma, as compared to non-cancerous liver tissue. We further identified that HepG2 cells present the same ligand/receptor pattern as human hepatocellular carcinomas. We investigated the role of APRIL in HepG2 gene expression in a time course study.
2011-05-20 | GSE29375 | GEO
Project description:Here we show that TACI-S increases its expression with maturation and colocalizes in the intracellular compartment with the ligand APRIL. APRIL downregulation in human B cells, eliminated class switch. These studies suggest the importance of intracellular APRIL together with TACI-S in maintaining humoral immunity.
2023-09-22 | GSE213981 | GEO
Project description:Chimeric antigen receptor T-cells (CAR-T) targeting B-cell-maturating-antigen (TNRFSF17, BCMA) show unprecedented overall response rates of up to 100% in heavily pretreated relapsed-refractory Multiple Myeloma (RRMM). However, the efficiency of the treatment is hindered by the rapid emergence of tumor-intrinsic mechanisms of resistance. We herein describe a patient with RRMM and extramedullary disease (EMD) who underwent Idecabtagene vicleucel BCMA CAR-T therapy. The patient rapidly achieved very good partial response including full resolution of EMD, but aggressively relapsed 5 months after CAR T cell infusion. Single cell RNA sequencing and immunohistochemistry on the re-emerging tumor cells demonstrated loss of target expression on mRNA and protein levels, and whole genome sequencing revealed the homozygous deletion of Chr 16p1313, including the BCMA locus. Clonal heterogeneity of BCMA could be observed in 32 RRMM patients from our institution. In three of them heterozygous deletion of BCMA could be confirmed, with none of them having underwent prior anti-BCMA therapy. Thus, our report not only provides first evidence of BCMA loss as the underlying mechanism of disease relapse following BCMA targeted immunotherapy in MM. It furthermore identifies a subset of patients at risk to develop biallelic BCMA inactivation thus linking genomic instability in MM to relapse from targeted immunotherapies.
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Project description:Emerging clinical evidence points to a function for B cell activating factor (BAFF) in pregnancy. However, a direct role for BAFF-axis members including BAFF, the closely related a proliferation-inducing ligand (APRIL), and their respective receptors in pregnancy has not been examined. This study demonstrates that loss of BAFF results in decreased inflammatory responsiveness and decreased susceptibility to inflammation-induced preterm birth (PTB). In contrast, loss of APRIL increases inflammatory responsiveness and susceptibility to PTB. Consistent with overlapping receptor utilization by BAFF and APRIL, deletion of BAFF-axis receptors is not sufficient to modify susceptibility to PTB. Critically, therapeutic administration of BAFF/APRIL monoclonal antibodies or recombinant proteins is sufficient to manipulate susceptibility to inflammation-induced PTB. Further, macrophages are identified as the principle BAFF producing immune cells at the maternal-fetal interface and BAFF and APRIL divergently manipulate macrophage gene expression and inflammatory function. Genes linked to labor initiation are upregulated in WT and APRIL deficient macrophages while downregulated in BAFF deficient macrophages and correlate with myeloid gene expression in human placental samples during labor. Thus, BAFF and APRIL play important, but divergent, counterregulatory inflammatory roles in pregnancy and provide new therapeutic targets for mitigating the risk of PTB.
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Project description:Anthony Nolan submissions to the IPD-IMGT/HLA Database from April 2020 to April 2021
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Project description:Antibody secreting cells (ASCs) survive in niche microenvironments, but cellular responses driven by particular niche signals are incompletely defined. The TNF superfamily (TNFSF) member A proliferation-inducing ligand (APRIL) can support the maturation of transitory plasmablasts into long-lived plasma cells. Here we explore the biological programs established by APRIL in human plasmablast. Under conditions allowing the maturation of ex vivo or in vitro generated plasmablasts, we find that APRIL drives activation of ERK, p38 and JNK, accompanied by a classical NFκB response and activation of the AKT/FOXO1 pathway. Time course gene expression data resolve co-ordinated transcriptional responses propagated via immediate early genes and NFκB targets and converging onto modules of genes enriched for MYC-targets and metabolism and cell growth related pathways. This response is shared between APRIL and an alternate TNFSF member CD40L but is not a feature of alternative niche signals delivered by IFNα or SDF1. However, APRIL and CD40L responses also diverge. CD40L drives expression of genes related to the activated B-cell state while APRIL does not. Thus, APRIL establishes a broad foundation for plasma cell longevity with features of cellular refuelling, while being uncoupled from support of the B-cell state.
2022-07-05 | GSE173644 | GEO
Project description:Antibody secreting cells (ASCs) survive in niche microenvironments, but cellular responses driven by particular niche signals are incompletely defined. The TNF superfamily (TNFSF) member A proliferation-inducing ligand (APRIL) can support the maturation of transitory plasmablasts into long-lived plasma cells. Here we explore the biological programs established by APRIL in human plasmablast. Under conditions allowing the maturation of ex vivo or in vitro generated plasmablasts, we find that APRIL drives activation of ERK, p38 and JNK, accompanied by a classical NFκB response and activation of the AKT/FOXO1 pathway. Time course gene expression data resolve co-ordinated transcriptional responses propagated via immediate early genes and NFκB targets and converging onto modules of genes enriched for MYC-targets and metabolism and cell growth related pathways. This response is shared between APRIL and an alternate TNFSF member CD40L but is not a feature of alternative niche signals delivered by IFNα or SDF1. However, APRIL and CD40L responses also diverge. CD40L drives expression of genes related to the activated B-cell state while APRIL does not. Thus, APRIL establishes a broad foundation for plasma cell longevity with features of cellular refuelling, while being uncoupled from support of the B-cell state.
2022-07-05 | GSE205100 | GEO
Project description:B-cell maturation antigen (BCMA) is a prominent tumor-associated target for chimeric antigen receptor (CAR)-T cell therapy in multiple myeloma (MM). We describe the case of a MM patient, enrolled in the CARTITUDE-1 trial (NCT03548207), who developed a progressive movement disorder with features of parkinsonism approximately three months after BCMA-targeted ciltacabtagene autoleucel CAR-T cell infusion, associated with CAR-T cell persistence in the blood and cerebrospinal fluid, and basal ganglia lymphocytic infiltration. We demonstrate BCMA expression on neurons and astrocytes in the basal ganglia of the patient. Public transcriptomic datasets further confirm BCMA RNA expression in the caudate of normal human brains, suggesting this may be an on-target effect of anti-BCMA therapy. Given reports of three patients with grade ≥3 parkinsonism on the phase 2 cilta-cel trial and of grade 3 parkinsonism in the idecabtagene vicleucel (ide-cel) package insert, our findings support close neurological monitoring of patients on BCMA-targeted T cell therapies.
2021-08-27 | GSE182527 | GEO