| First Author | Reimann M | Year | 2021 |
| Journal | Blood | Volume | 137 |
| Issue | 20 | Pages | 2785-2799 |
| PubMed ID | 33232972 | Mgi Jnum | J:307791 |
| Mgi Id | MGI:6724690 | Doi | 10.1182/blood.2020005244 |
| Citation | Reimann M, et al. (2021) Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas. Blood 137(20):2785-2799 |
| abstractText | Aberrant B-cell receptor/NF-kappaB 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-kappaB, 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 Emicro-myc transgenic hematopoietic stem cells stably transduced with naturally occurring NF-kappaB 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. However, MyD88- or CARD11-mutant Emicro-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. |
