Small-molecule BCL6 inhibitor effectively treats mice with nonsclerodermatous chronic graft-versus-host disease

Abstract

Patient outcomes for steroid-dependent or -refractory chronic graft-versus-host diesease (cGVHD) are poor, and only ibrutinib has been US Food and Drug Administration (FDA) approved for this indication. cGVHD is often driven by the germinal center (GC) reaction, in which T follicular helper cells interact with GC B cells to produce antibodies that are associated with disease pathogenesis. The transcriptional corepressor B-cell lymphoma 6 (BCL6) is a member of the Broad-complex, Tramtrack, and Bric-abrac/poxvirus and zinc finger (BTB/POZ) transcription factor family and master regulator of the immune cells in the GC reaction. We demonstrate that BCL6 expression in both donor T cells and B cells is necessary for cGVHD development, pointing to BCL6 as a therapeutic cGVHD target. A small-molecule BCL6 inhibitor reversed active cGVHD in a mouse model of multiorgan system injury with bronchiolitis obliterans associated with a robust GC reaction, but not in cGVHD mice with scleroderma as the prominent manifestation. For cGVHD patients with antibody-driven cGVHD, targeting of BCL6 represents a new approach with specificity for a master GC regulator that would extend the currently available second-line agents.

C5aR1 regulates T follicular helper differentiation and chronic graft-versus-host disease bronchiolitis obliterans

“…BR→BALB/c model of scleroderma, a disease that is principally attributed to Th17 alloimmunity and not autoantibody (52). These data are consistent with previous work in which we showed that a small-molecule BCL6 peptidomimetic functioned as a potent inhibitor in the BOS model but had no effect in the same scleroderma system, as reported in this manuscript (25). Coupled with the observations that pharmacological syk inhibition potently affects Tfh cell-dependent chronic GvHD in mice and is efficacious in human chronic GvHD, yet has little clinical benefit in the scleroderma model (53), our findings suggest that C5aR1 inhibition preferentially restrains Tfh cell-dependent GC formation when administered after disease initiation.…”

“…Coupled with the observations that pharmacological syk inhibition potently affects Tfh cell-dependent chronic GvHD in mice and is efficacious in human chronic GvHD, yet has little clinical benefit in the scleroderma model (53), our findings suggest that C5aR1 inhibition preferentially restrains Tfh cell-dependent GC formation when administered after disease initiation. These observations build upon prior murine studies in which chronic GvHD could be reversed by targeted GC disruption using a lymphotoxin-β fusion protein (54) or administering T cells or bone marrow as a source of B cells defective in supporting GC formation (25,43,(53)(54)(55). Relevant to human chronic GvHD patients, serum CXCL13 levels are elevated (44) and are associated with low Tfh cell numbers in peripheral blood (44,53), suggesting that circulating Tfh cells have been recruited into GCs where high-affinity antibody-secreting cells can be generated.…”

“…We also tested the therapeutic efficacy of C5aR1-A administration in the B10.D2→BALB/c model of chronic GvHD that recapitulates many clinical characteristics of scleroderma (25,45). Previous studies have shown that scleroderma pathogenesis in this system involves CD4 + Th17 cells as well as STAT3 signaling (46), without clear evidence for involvement of Tfh cell-dependent GCs (25,45). Therapeutic administration of C5aR1-A beginning on day 14 (after clinical manifestations of the disease have initiated) had no effect on the progression of the scleroderma phenotype ( Figure 5I).…”

“…Chronic GvHD, a significant long-term complication that affects approximately 30%-70% of allogeneic blood/marrow recipients, manifests pathologically with inflammation-initiated fibrosis that can involve virtually all organs in the body, including the gastrointestinal tract, joints, mouth, eyes, lungs (bronchiolitis obliterans syndrome [BOS]), liver, and skin (16)(17)(18)(19). Current concepts also support pathogenic roles for innate immune cells (20)(21)(22) and Th17, Th1, and Th2 cells as well as Tfh cells (regulated by Tfr cells); each have been linked to chronic GvHD (16,(23)(24)(25). The latter induce pathogenic IgG, alloantibodies, and/or autoantibodies and together with the T cells, and macrophages initiate a fibrogenic program that results in chronic organ injury in GvHD settings in which potentially pathogenic antibodies have been detected (16,18,24,26).…”

GITR Agonism Triggers Antitumor Immune Responses through IL21-Expressing Follicular Helper T Cells

“…6A). To inhibit Tfh cell responses, we used the small-molecule inhibitor 79-6, which inhibits transcription factor Bcl6 (39,40). Treatment with 79-6 decreased IL21 production in IL4-and DTA-1stimulated na€ ve CD4 þ T cells without inducing cellular cytotoxicity ( Fig.…”