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| Item Type: | Article |
|---|---|
| Title: | Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas |
| Creators: |
Reimann, M.  ORCID: https://orcid.org/0000-0002-7876-0128, Schrezenmeier, J.F. ORCID: https://orcid.org/0000-0001-5239-4513, Richter-Pechanska, P. ORCID: https://orcid.org/0000-0001-6727-6317, Dolnik, A., Hick, T.P., Schleich, K., Cai, X., Fan, D.N.Y. ORCID: https://orcid.org/0000-0001-6826-7076, Lohneis, P., Masswig, S., Denker, S. ORCID: https://orcid.org/0000-0002-0736-6019, Busse, A. ORCID: https://orcid.org/0000-0002-3470-6947, Knittel, G., Flümann, R., Childs, D., Childs, L., Gätjens-Sanchez, A.M., Bullinger, L. ORCID: https://orcid.org/0000-0002-5890-5510, Rosenwald, A., Reinhardt, H.C. and Schmitt, C.A. ORCID: https://orcid.org/0000-0002-4731-2226
|
| Abstract: | 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. |
| Keywords: | Activated B-Cell (ABC), CARD11, Cell-of-Origin (COO), Cellular Senescence, Diffuse Large B-Cell Lymphoma (DLBCL), Germinal Center B-Cell (GCB), Immune Checkpoint, Macrophages, Mouse Models, MyD88, NF-κB Signaling, Stroma, T-Cell Immunity, Animals, Mice |
| Source: | Blood |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Volume: | 137 |
| Number: | 20 |
| Page Range: | 2785-2899 |
| Date: | 20 May 2021 |
| Official Publication: | https://doi.org/10.1182/blood.2020005244 |
| PubMed: | View item in PubMed |
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