Genetically driven immune microenvironment states associate with therapeutic responses in MYD88 mutant lymphomas [WES]

Here we utilized murine models with oncogenically active MYD88 and additional genetic lesions co-triggered at selected B-cell stages to generate human-like lymphomas harboring MYD88L265P mutation. Lymphomas exhibited behaviors ranging from clinically indolent small-cell tumors to aggressive diffuse large B-cell lymphoma (DLBCL).

Thus, genetically diverse lymphoma cells employed distinct immune evasion mechanisms that shaped unique lymphoma microenvironment (LME) states, whereby clonally expanded T-cells functioned as a double-edged sword, either sustaining indolent lymphoma cell survival or promoting antitumor responses in DLBCL. Consequently, efficacy of standard-of-care and novel immunotherapies was determined by individual T-cell features. Furthermore, experimental targeting of newly identified immune mechanisms improved therapeutic responses in vivo.