Uncovering regulatory B‐cell features associated with regulatory T‐cell expansion and global T‐cell exhaustion in Waldenström macroglobulinemia <i>Myd88</i> ^<i>L252P</i> ‐like lymphoplasmacytic lymphomas

Waldenström's macroglobulinemia (WM) is a rare, indolent lymphoproliferative disorder, genetically characterized by the presence of the <i>L265P</i> mutation in the <i>MYD88</i> gene in almost all cases, resulting in constitutive activation of NF-kappa B (NF-κB). Despite its slow progression, WM remains incurable due to the lack of specific treatments. The efficacy of therapies capable of reactivating the antitumor response of T-cells is well documented in various solid tumors. Apart from Hodgkin's lymphoma, these therapies have very mixed effects on B-cell lymphomas, especially those with NF-κB activation. Here, we used the published <i>Myd88</i> ^<i>L252P</i> mouse model, which develops a WM-like disease close to human WM. By focusing on T-cell exhaustion and regulatory T-cell expansion, we show how T-cells located near WM-like tumors in mice are disrupted, while <i>Myd88</i> ^<i>L252P</i> tumor B-cells adopt an immunoregulatory phenotype evoking regulatory B-cells. We also demonstrate, for the first time in the context of WM, the dual effect of Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK), able to decrease B-cell activation and expansion and to partially reverse T-cell depletion in <i>Myd88</i> ^<i>L252P</i> mice. With Ibrutinib as an example, this work provides new perspectives for the development of therapeutic combinations targeting tumor B-cells while reactivating antitumor T-cells.