Recent investigations have improved our understanding of the molecular aberrations supporting Waldenström macroglobulinemia (WM) biology; however, whether the immune microenvironment contributes to WM pathogenesis remains unanswered. First, we showed how a transgenic murine model of human-like lymphoplasmacytic lymphoma/WM exhibits an increased number of regulatory T cells (Tregs) relative to control mice. These findings were translated into the WM clinical setting, in which the transcriptomic profiling of Tregs derived from patients with WM unveiled a peculiar WM-devoted messenger RNA signature, with significant enrichment for genes related to nuclear factor κB–mediated tumor necrosis factor α signaling, MAPK, and PI3K/AKT, which was paralleled by a different Treg functional phenotype. We demonstrated significantly higher Treg induction, expansion, and proliferation triggered by WM cells, compared with their normal cellular counterpart; with a more profound effect within the context of CXCR4C1013G-mutated WM cells. By investigating the B-cell–to–T-cell cross talk at single-cell level, we identified the CD40/CD40-ligand as a potentially relevant axis that supports WM cell–Tregs interaction. Our findings demonstrate the existence of a Treg-mediated immunosuppressive phenotype in WM, which can be therapeutically reversed by blocking the CD40L/CD40 axis to inhibit WM cell growth.

Sacco, A., Desantis, V., Celay, J., Giustini, V., Rigali, F., Savino, F., et al. (2023). Targeting the immune microenvironment in Waldenström Macroglobulinemia via halting the CD40/CD40-ligand axis. BLOOD, 141(21), 2615-2628 [10.1182/blood.2022019240].

Targeting the immune microenvironment in Waldenström Macroglobulinemia via halting the CD40/CD40-ligand axis

D'Aliberti, Deborah;Spinelli, Silvia;Ramazzotti, Daniele;Piazza, Rocco;
2023

Abstract

Recent investigations have improved our understanding of the molecular aberrations supporting Waldenström macroglobulinemia (WM) biology; however, whether the immune microenvironment contributes to WM pathogenesis remains unanswered. First, we showed how a transgenic murine model of human-like lymphoplasmacytic lymphoma/WM exhibits an increased number of regulatory T cells (Tregs) relative to control mice. These findings were translated into the WM clinical setting, in which the transcriptomic profiling of Tregs derived from patients with WM unveiled a peculiar WM-devoted messenger RNA signature, with significant enrichment for genes related to nuclear factor κB–mediated tumor necrosis factor α signaling, MAPK, and PI3K/AKT, which was paralleled by a different Treg functional phenotype. We demonstrated significantly higher Treg induction, expansion, and proliferation triggered by WM cells, compared with their normal cellular counterpart; with a more profound effect within the context of CXCR4C1013G-mutated WM cells. By investigating the B-cell–to–T-cell cross talk at single-cell level, we identified the CD40/CD40-ligand as a potentially relevant axis that supports WM cell–Tregs interaction. Our findings demonstrate the existence of a Treg-mediated immunosuppressive phenotype in WM, which can be therapeutically reversed by blocking the CD40L/CD40 axis to inhibit WM cell growth.
Articolo in rivista - Articolo scientifico
Waldenström Macroglobulinemia
English
3-feb-2023
2023
141
21
2615
2628
none
Sacco, A., Desantis, V., Celay, J., Giustini, V., Rigali, F., Savino, F., et al. (2023). Targeting the immune microenvironment in Waldenström Macroglobulinemia via halting the CD40/CD40-ligand axis. BLOOD, 141(21), 2615-2628 [10.1182/blood.2022019240].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/403075
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