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Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas

Item Type:Article
Title:Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas
Creators Name:Reimann, M. and Schrezenmeier, J.F. and Richter-Pechanska, P. and Dolnik, A. and Hick, T.P. and Schleich, K. and Cai, X. and Fan, D.N.Y. and Lohneis, P. and Masswig, S. and Denker, S. and Busse, A. and Knittel, G. and Flümann, R. and Childs, D. and Childs, L. and Gätjens-Sanchez, A.M. and Bullinger, L. and Rosenwald, A. and Reinhardt, H.C. and Schmitt, C.A.
Abstract:Aberrant B-cell receptor (BCR)/NF-κB signaling is a hallmark feature of B-cell non-Hodgkin lymphomas (B-NHL), especially in diffuse large B-cell lymphoma (DLBCL). Recurrent mutations in this cascade, e.g. in CD79B, CARD11, or NFKBIZ, and also in the Toll-like receptor pathway transducer MyD88, all deregulate NF-κB, but their differential impact on lymphoma development and biology remains to be determined. We functionally investigate here primary mouse lymphomas that formed in recipient mice of Eµ-myc transgenic hematopoietic stem cells (HSC) stably transduced with naturally occurring NF-κB mutants. While most mutants supported Myc-driven lymphoma formation through repressed apoptosis, CARD11- or MyD88-mutant lymphoma cells selectively presented with a macrophage-activating secretion profile, which, in turn, strongly enforced TGF-β-mediated senescence in the lymphoma cell compartment. However, MyD88- or CARD11-mutant Eµ-myc lymphomas exhibited high-level expression of the immune checkpoint mediator PD-L1, thus preventing their efficient clearance by adaptive host immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti-PD1 checkpoint blockade, leading to direct T-cell-mediated lysis of predominantly but not exclusively senescent lymphoma cells. Importantly, mouse-based mutant MyD88- and CARD11-derived signatures marked DLBCL subgroups exhibiting mirroring phenotypes with respect to the triad of senescence induction, macrophage attraction, and evasion of cytotoxic T-cell immunity. Complementing genomic subclassification approaches, our functional, cross-species investigation unveils pathogenic principles and therapeutic vulnerabilities applicable to and testable in human DLBCL subsets that may inform future personalized treatment strategies.
Keywords:Activated B-Cell (ABC), CARD11, Cell-of-Origin (COO), Cellular Senescence, Diffuse Large B-Cell Lymphoma (DLBCL), Germinal Center B-Cell (GCB), Immune Checkpoint, Macrophages, Mouse Models, MyD88, NF-κB Signaling, Stroma, T-Cell Immunity, Animals, Mice
Publisher:American Society of Hematology
Page Range:2785-2899
Date:20 May 2021
Official Publication:https://doi.org/10.1182/blood.2020005244
PubMed:View item in PubMed

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