Details

Autor(en) / Beteiligte

• Reimann, Maurice
• Schrezenmeier, Jens
• Richter-Pechanska, Paulina
• Dolnik, Anna
• Hick, Timon Pablo
• Schleich, Kolja
• Cai, Xiurong
• Fan, Dorothy N.Y.
• Lohneis, Philipp
• Maßwig, Sven
• Denker, Sophy
• Busse, Antonia
• Knittel, Gero
• Flümann, Ruth
• Childs, Dorothee
• Childs, Liam
• Gätjens-Sanchez, Ana-Maria
• Bullinger, Lars
• Rosenwald, Andreas
• Reinhardt, Hans Christian
• Schmitt, Clemens A.

Titel

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

Ist Teil von

• Blood, 2021-05, Vol.137 (20), p.2785-2799

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. •The CARD11- or MyD88-mutant Eµ-myc– transgenic lymphoma secretome activates macrophages to mediate lymphoma cell senescence via TGF-β.•MyD88- or CARD11-mutant lymphomas counter senescence-preferential T-cell recognition by PD-L1 expression, as seen in human DLBCL profiles. [Display omitted]