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

Tools

Item Type:	Article
Title:	Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas
Creators Name:	Reimann, M., Schrezenmeier, J.F., Richter-Pechanska, P., Dolnik, A., Hick, T.P., Schleich, K., Cai, X., Fan, D.N.Y., Lohneis, P., Masswig, S., Denker, S., Busse, A., Knittel, G., Flümann, R., Childs, D., Childs, L., Gätjens-Sanchez, A.M., Bullinger, L., Rosenwald, A., 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
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	137
Number:	20
Page Range:	2785-2899
Date:	20 May 2021
Official Publication:	https://doi.org/10.1182/blood.2020005244
PubMed:	View item in PubMed

Repository Staff Only: item control page