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

Aberrant B-cell receptor/NF-kB 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-kB, but their differential impact on lym-phoma development and biology remains to be determined. Here, we functionally investigate primary mouse lymphomas that formed in recipient mice of Emmyc transgenic hematopoietic stem cells stably transduced with naturally occurring NF-kappa B 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 beta (TGF-beta)-mediated senescence in the lymphoma cell compartment. How-ever, MyD88- or CARD11-mutant Em-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 check-point 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.

Automated summary

The aberrant B-cell receptor/NF-kB signaling is a hallmark feature of B-cell non-Hodgkin lymphomas, especially in diffuse large B-cell lymphoma (DLBCL). Mutations in CD79B, CARD11, NFKBIZ, and MyD88 deregulate NF-kB but their differential impact on lymphoma development remains to be fully understood. Further investigation into primary mouse lymphomas revealed mutant-specific dependencies that were therapeutically exploitable by anti-programmed cell death 1 check-point blockade, providing insights into potential personalized treatment strategies for human DLBCL subsets.