Scientific publications
Targeting the immune microenvironment in Waldenström macroglobulinemia via halting the CD40/CD40-ligand axis. Scientific Publication
Antonio Sacco 1, Vanessa Desantis 2, Jon Celay 3, Viviana Giustini 1, Fabio Rigali 1, Francesco D Savino 1, Michele Cea 4, Debora Soncini 4, Antonia Cagnetta 4, Antonio G Solimando 5, Deborah D'Aliberti 6, Silvia Spinelli 6, Daniele Ramazzotti 6, Camillo Almici 7, Katia Todoerti 8, Antonino Neri 9, Antonella Anastasia 10, Alessandra Tucci 10, Marina Motta 10, Marco Chiarini 11, Yawara Kawano 12, Jose A Martinez-Climent 3, Rocco Piazza 6 13, Aldo M Roccaro 1
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.
CITATION Blood. 2023 May 25;141(21):2615-2628. doi: 10.1182/blood.2022019240.
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