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

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. We first showed how a transgenic murine model of human-like lymphoplasmacytic lymphoma/WM exhibits an increased number of regulatory T (Treg) cells with respect to control mice. These findings were translated into the WM clinical setting, where the transcriptomic profiling of WM patients'-derived regulatory T cells (Tregs) unveiled a peculiar WM-devoted mRNA signature, with significant enrichment for NF-kB-mediated TNF-a signaling-, MAPK-, PI3K/AKT-related genes; paralleled by different Treg functional phenotype. We demonstrated a significantly higher Treg-induction, -expansion and -proliferation triggered by WM cells as compared to their normal cellular counterpart; with a more profound effect within the context of CXCR4C1013G-mutated WM cells. By investigating the B-to-T cell cross-talk at single-cell level, we identified the CD40/CD40-ligand as a potentially relevant axis supporting WM cell-Treg cell 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.

B-cell specific expression of the murineMyd88L252Pmutation correlates with the establishment of an immunosuppressive microenvironnement in Waldenström macroglobulinemia lymphoplasmacytic lymphoma

“…We showed here that Tregs from MW-like tumours overexpressed the anti-inflammatory cytokines IL-10 and IL-6. This is in agreement with a recent study showing, in another mouse model and in patient, the existence of a Treg-mediated immunosuppressive phenotype in WM [28]. We also discovered in our mouse model, in comparison to control mice, an expansion of TIM-3 + Tregs cells which secreted higher amounts of immunosuppressive IL-6 and IL-10 cytokines than do TIM-3 -Tregs.…”

“…Targeting this population would then be a therapeutic prospect for WM. In this sense, Sacco et al propose to target the CD40/CD40L axis after having identified its role in the WM cell-Tregs interaction [28].…”

First-in-human clinical trial of personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma

“…2G ), rather than naïve cells primed by vaccine. Recent studies have suggested that Treg cells create an immunosuppressive milieu in WM, the most common subtype of LPL 69 . However, we observed no obvious changes in frequencies or signaling pathways in Treg that would suggest an effect of vaccination on this subpopulation ( Fig.…”

Navigating Lymphomas through BCR Signaling and Double-Hit Insights: Overview

“…Molecular and cytogenetic investigations can highlight characteristic chromosomal anomalies with both diagnostic, prognostic, and/or predictive significance. For example, the discovery that an activating mutation of MYD88 is associated with most cases of lymphoplasmacytic lymphoma has made it possible to develop an allele-specific PCR method useful for better understanding this neoplasm, which often presents with clinical and histopathological characteristics which overlap with other forms, such as MZL [ 19 , 20 ]. It should be underlined that molecular genetic tests must always be integrated into clinical, laboratory, and histopathological diagnostics since no molecular alteration in indolent lymphomas is pathognomonic of a single nosological entity [ 21 ].…”