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

Waldenström's macroglobulinemia (WM) is a rare, indolent lymphoproliferative disorder, genetically characterized by the presence of the L265P mutation in the MYD88 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 Myd88 L252P 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 Myd88 L252P 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 Myd88 L252P 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.