Pluto Biosciences, Inc

GSE141453: DLBCL-reminiscent MyD88- or CARD11-mutant aggressive B-cell lymphomas exhibit strong pro-senescent and immune-evasive phenotypes [part2]

Bulk RNA sequencing

Aberrant B-cell receptor (BCR)/NF-kB signaling activity is a prominent feature of diffuse large B-cell lymphoma (DLBCL), particularly of, but not restricted to the activated B-cell (ABC) subtype. Recurrent mutations in this cascade, e.g. in CD79B, CARD11, A20/TNFAIP3 or NFKBIZ, but also in the Toll-like receptor (TLR) pathway transducer MyD88, all converge at NF-kB deregulation, but their differential impact on lymphoma development and biology remains to be dissected. Recapitulating oncogenic myc rearrangements as another common feature of DLBCL, we functionally investigate here primary mouse lymphomas that formed after propagation of E-myc transgenic hematopoietic stem cells (HSC), stably transduced with naturally occurring DLBCL-derived NF-kB mutants, in recipient mice. While most mutants tested supported Myc-driven lymphoma formation through repressed apoptosis, selectively deregulated CARD11- or MyD88-mutant lymphoma cells presented with a macrophage-activating secretion profile, which, in turn, enforced TGF-b-mediated feedback senescence in the lymphoma cell compartment. Moreover, MyD88- or CARD11-mutant E-myc lymphomas mirrored by matching signatures in their mutant DLBCL counterparts exhibited high-level expression of the immune checkpoint mediator PD-L1, thus preventing their efficient clearance by adaptive host cell immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti-PD1 immune checkpoint blockade, leading to the direct T-cell-mediated lysis of predominantly but not exclusively senescent lymphoma cells. Our functional, cross-species interrogation of a syngeneic and fully immune-competent, BCR/NF-kB-deregulated and DLBCL-reminiscent in vivo-model platform unveils common principles and therapeutic vulnerabilities related to human DLBCL subsets that will inform future personalized treatment strategies. Specifically, for the shown FLC transplantation experiments, 8-12 week-old female C57BL/6N recipient mice (Charles River Laboratories) received a single, myelo-ablative dose of 9 Gy total-body gamma-irradiation. After in vitro-transduction of FLC, 10% GFP-positive Sca1+; c-Kit+; lin- cells with the indictaed transgenic and/or knock out genotypes were transplanted via tail vein injection into irradiated mice, which were subsequently monitored until a well-palpable lymphadenopathy had formed. Retroviral vectors used in this experiment were the MSCV 2.2 derived constructs SOURCE: Anna Dolnik (anna.dolnik@charite.de) - Hämatologie, Onkologie und Tumorimmunologie Charité Universitätsmedizin Berlin

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