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Project description:Aberrant B-cell receptor (BCR)/NF-kB signaling activity is a prominent feature of diffuse large B-cell lymphoma (DLBCL), particularly of, but not restricted to the activated B-cell (ABC) subtype. Recurrent mutations in this cascade, e.g. in CD79B, CARD11, A20/TNFAIP3 or NFKBIZ, but also in the Toll-like receptor (TLR) pathway transducer MyD88, all converge at NF-kB deregulation, but their differential impact on lymphoma development and biology remains to be dissected. Recapitulating oncogenic myc rearrangements as another common feature of DLBCL, we functionally investigate here primary mouse lymphomas that formed after propagation of Eµ-myc transgenic hematopoietic stem cells (HSC), stably transduced with naturally occurring DLBCL-derived NF-kB mutants, in recipient mice. While most mutants tested supported Myc-driven lymphoma formation through repressed apoptosis, selectively deregulated CARD11- or MyD88-mutant lymphoma cells presented with a macrophage-activating secretion profile, which, in turn, enforced TGF-b-mediated feedback senescence in the lymphoma cell compartment. Moreover, MyD88- or CARD11-mutant Eµ-myc lymphomas – mirrored by matching signatures in their mutant DLBCL counterparts – exhibited high-level expression of the immune checkpoint mediator PD-L1, thus preventing their efficient clearance by adaptive host cell immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti-PD1 immune checkpoint blockade, leading to the direct T-cell-mediated lysis of predominantly but not exclusively senescent lymphoma cells. Our functional, cross-species interrogation of a syngeneic and fully immune-competent, BCR/NF-kB-deregulated and DLBCL-reminiscent in vivo-model platform unveils common principles and therapeutic vulnerabilities related to human DLBCL subsets that will inform future personalized treatment strategies. Specifically, for the shown FLC transplantation experiments, 8-12 week-old female C57BL/6N recipient mice (Charles River Laboratories) received a single, myelo-ablative dose of 9 Gy total-body gamma-irradiation. After in vitro-transduction of FLC, 10% GFP-positive Sca1+; c-Kit+; lin- cells with the indictaed transgenic and/or knock out genotypes were transplanted via tail vein injection into irradiated mice, which were subsequently monitored until a well-palpable lymphadenopathy had formed. Retroviral vectors used in this experiment were the MSCV 2.2 derived constructs
2020-12-07 | GSE141453 | GEO
Project description:Aberrant B-cell receptor (BCR)/NF-kB signaling activity is a prominent feature of diffuse large B-cell lymphoma (DLBCL), particularly of, but not restricted to the activated B-cell (ABC) subtype. Recurrent mutations in this cascade, e.g. in CD79B, CARD11, A20/TNFAIP3 or NFKBIZ, but also in the Toll-like receptor (TLR) pathway transducer MyD88, all converge at NF-kB deregulation, but their differential impact on lymphoma development and biology remains to be dissected. Recapitulating oncogenic myc rearrangements as another common feature of DLBCL, we functionally investigate here primary mouse lymphomas that formed after propagation of Eµ-myc transgenic hematopoietic stem cells (HSC), stably transduced with naturally occurring DLBCL-derived NF-kB mutants, in recipient mice. While most mutants tested supported Myc-driven lymphoma formation through repressed apoptosis, selectively deregulated CARD11- or MyD88-mutant lymphoma cells presented with a macrophage-activating secretion profile, which, in turn, enforced TGF-b-mediated feedback senescence in the lymphoma cell compartment. Moreover, MyD88- or CARD11-mutant Eµ-myc lymphomas – mirrored by matching signatures in their mutant DLBCL counterparts – exhibited high-level expression of the immune checkpoint mediator PD-L1, thus preventing their efficient clearance by adaptive host cell immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti-PD1 immune checkpoint blockade, leading to the direct T-cell-mediated lysis of predominantly but not exclusively senescent lymphoma cells. Our functional, cross-species interrogation of a syngeneic and fully immune-competent, BCR/NF-kB-deregulated and DLBCL-reminiscent in vivo-model platform unveils common principles and therapeutic vulnerabilities related to human DLBCL subsets that will inform future personalized treatment strategies.
2020-12-07 | GSE141452 | GEO
Project description:DLBCL-reminiscent MyD88- or CARD11-mutant aggressive B-cell lymphomas exhibit strong pro-senescent and immune-evasive phenotypes
| PRJNA593515 | ENA
Project description:DLBCL-reminiscent MyD88- or CARD11-mutant aggressive B-cell lymphomas exhibit strong pro-senescent and immune-evasive phenotypes [part1]
| PRJNA593522 | ENA
Project description:DLBCL-reminiscent MyD88- or CARD11-mutant aggressive B-cell lymphomas exhibit strong pro-senescent and immune-evasive phenotypes [part2]
| PRJNA593523 | ENA
Project description:BackgroundGlioma stem cells (GSCs) have self-renewal and tumor-initiating capacities involved in drug resistance and immune evasion mechanisms in glioblastoma (GBM).MethodsCore-GSCs (c-GSCs) were identified by selecting cells co-expressing high levels of embryonic stem cell (ESC) markers from a single-cell RNA-seq patient-derived GBM dataset (n = 28). Induced c-GSCs (ic-GSCs) were generated by reprogramming GBM-derived cells (GBM-DCs) using induced pluripotent stem cell (iPSC) technology. The characterization of ic-GSCs and GBM-DCs was conducted by immunostaining, transcriptomic, and DNA methylation (DNAm) analysis.ResultsWe identified a GSC population (4.22% ± 0.59) exhibiting concurrent high expression of ESC markers and downregulation of immune-associated pathways, named c-GSCs. In vitro ic-GSCs presented high expression of ESC markers and downregulation of antigen presentation HLA proteins. Transcriptomic analysis revealed a strong agreement of enriched biological pathways between tumor c-GSCs and in vitro ic-GSCs (κ = 0.71). Integration of our epigenomic profiling with 833 functional ENCODE epigenetic maps identifies increased DNA methylation on HLA genes' regulatory regions associated with polycomb repressive marks in a stem-like phenotype.ConclusionsThis study unravels glioblastoma immune-evasive mechanisms involving a c-GSC population. In addition, it provides a cellular model with paired gene expression, and DNA methylation maps to explore potential therapeutic complements for GBM immunotherapy.
| S-EPMC9104850 | biostudies-literature
Project description:The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from 13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known (ATM, MEF2B and MLL2) and novel mutation targets (S1PR1 and CARD11). CARD11, a scaffold protein required for B-cell receptor (BCR)-induced NF-κB activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-κB-inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-κB activation in a subset of MCL.
| S-EPMC5122381 | biostudies-literature
Project description:Most patients with aggressive non-Hodgkin lymphoma will be cured with initial chemoimmunotherapy; however, most patients with relapsed disease will not be cured and will die as a result of their disease. In these cases, continued treatment with conventional chemotherapy is typically not of benefit and can contribute to significant toxicities and decreased quality of life for patients. Fortunately, a number of therapies are currently available or under investigation for this group of patients, ranging from oral tyrosine kinase inhibitors targeting multiple pathways within the malignant cells to adoptive cellular therapies that harness the patient's immune system to fight disease. Additionally, many agents that are modestly effective as monotherapies can be safely combined with additional novel and conventional therapies to improve response rates and duration. Chimeric antigen receptor T cells are among the most promising group of therapies and provide the potential for cure for patients with relapsed/refractory lymphoma. In this chapter, we will review the currently available novel treatments as well as those still under investigation and discuss the most appropriate approach to patients with relapsed/refractory aggressive lymphoma. We will highlight the challenges associated with these therapies, as well as potential toxicities, and the need for additional clinical trials evaluating combinations and newer treatments.
| S-EPMC6245978 | biostudies-literature
Project description:CD19 directed chimeric antigen receptor T-cell therapy (CAR-T) represents a significant advancement for patients with relapsed/refractory large B-cell lymphoma (LBCL). Long term follow-up confirms durable remissions in nearly half of the patients, a population which was previously estimated to have a median survival of around 6 months with standard salvage therapy. This initial success of CAR-T has led to significant expansion across other lymphoma histologies resulting in the recent regulatory approval of CAR-T in mantle cell lymphoma and follicular lymphoma. Additionally, multiple novel platforms of CAR-T therapy are under development to improve efficacy and limit toxicity such dual antigen targeting, allogeneic and natural killer CAR's. In this review, we focus on the new indications of CAR-T in lymphomas beyond LBCL as well as emerging platforms of CAR-T therapy.
| S-EPMC8725814 | biostudies-literature
Project description: Not available
| S-EPMC7302956 | biostudies-literature