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


  • M. Reimann
  • J.F. Schrezenmeier
  • P. Richter-Pechanska
  • A. Dolnik
  • T.P. Hick
  • K. Schleich
  • X. Cai
  • D.N.Y. Fan
  • P. Lohneis
  • S. Masswig
  • S. Denker
  • A. Busse
  • G. Knittel
  • R. Flümann
  • D. Childs
  • L. Childs
  • A.M. Gätjens-Sanchez
  • L. Bullinger
  • A. Rosenwald
  • H.C. Reinhardt
  • C.A. Schmitt


  • Blood


  • Blood


  • 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.