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

• Published in: Blood 2023-05, Vol.141 (21), p.2615-2628
• Main Authors: Sacco, Antonio, Desantis, Vanessa, Celay, Jon, Giustini, Viviana, Rigali, Fabio, Savino, Francesco D., Cea, Michele, Soncini, Debora, Cagnetta, Antonia, Solimando, Antonio G., D’Aliberti, Deborah, Spinelli, Silvia, Ramazzotti, Daniele, Almici, Camillo, Todoerti, Katia, Neri, Antonino, Anastasia, Antonella, Tucci, Alessandra, Motta, Marina, Chiarini, Marco, Kawano, Yawara, Martinez-Climent, Jose A., Piazza, Rocco, Roccaro, Aldo M.
• Format: Article
• Language: English
• Subjects: Animals; CD40 Ligand - genetics; Humans; Ligands; Lymphoma, B-Cell - complications; Mice; Phosphatidylinositol 3-Kinases; Signal Transduction; Tumor Microenvironment; Waldenstrom Macroglobulinemia - pathology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022019240

•A CD40/CD40-ligand interaction mediates WM cell–Tregs cross talk.•Blocking the CD40/CD40-ligand axis inhibits Treg-mediated immunosuppression and reduces WM cell growth. [Display omitted] 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. There is increasing attention focused on the immune microenvironment of lymphoid malignancies that appears to protect tumor cells from immune attack. Sacco and colleagues address this question in Waldenström macroglobulinemia (WM). Transcriptomic profiling in a murine model of WM with confirmation in patient samples demonstrated increased regulatory T (Treg) cells with a characteristic signature that is induced and expanded in WM. The authors further identified crosstalk between WM cells and Tregs supported by CD40/CD40 ligand, identifying a potential clinical target for inhibiting WM growth.