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

Blood. 2021 May 20;137(20):2785-2799. doi: 10.1182/blood.2020005244.


Aberrant B-cell receptor/NF-κB signaling is a hallmark feature of B-cell non-Hodgkin lymphomas, especially in diffuse large B-cell lymphoma (DLBCL). Recurrent mutations in this cascade, for example, 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. Here, we functionally investigate primary mouse lymphomas that formed in recipient mice of Eµ-myc transgenic hematopoietic stem cells stably transduced with naturally occurring NF-κB mutants. Although 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 transforming growth factor β (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 programmed cell death ligand 1 (PD-L1), thus preventing their efficient clearance by adaptive host immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti-programmed cell death 1 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity*
  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • B7-H1 Antigen / antagonists & inhibitors
  • CARD Signaling Adaptor Proteins / genetics*
  • CD79 Antigens / genetics
  • Cell Line, Tumor
  • Cellular Senescence / physiology*
  • Chemotaxis
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Genes, Reporter
  • Genes, myc
  • Guanylate Cyclase / genetics*
  • Humans
  • Immune Checkpoint Inhibitors
  • Lymphoma, Large B-Cell, Diffuse / immunology*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Lymphoma, Large B-Cell, Diffuse / therapy
  • Macrophages / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation, Missense
  • Myeloid Differentiation Factor 88 / genetics*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasm Proteins / genetics*
  • Point Mutation
  • Programmed Cell Death 1 Ligand 2 Protein / antagonists & inhibitors
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transcriptome


  • Adaptor Proteins, Signal Transducing
  • B7-H1 Antigen
  • CARD Signaling Adaptor Proteins
  • CD79 Antigens
  • Card11 protein, mouse
  • Cd274 protein, mouse
  • Cd79b protein, mouse
  • Immune Checkpoint Inhibitors
  • MYD88 protein, human
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Neoplasm Proteins
  • Nfkbiz protein, mouse
  • Pdcd1lg2 protein, mouse
  • Programmed Cell Death 1 Ligand 2 Protein
  • RNA, Neoplasm
  • CARD11 protein, human
  • Guanylate Cyclase