Genetically driven immune microenvironment states associate with therapeutic responses in MYD88 mutant lymphomas.

The interaction between lymphoma cells and immune microenvironment cells and the impact of this functional interplay on therapeutic responses remain largely unexplored. 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 the MYD88L265P mutation. Lymphomas exhibited behaviors ranging from clinically indolent small-cell tumors to aggressive diffuse large B-cell lymphoma (DLBCL). Genetically diverse lymphoma cells employ distinct immune evasion mechanisms that shape unique lymphoma microenvironment (LME) states. In this setting, clonally expanded T-cells function as a double-edged sword, either sustaining indolent lymphoma cell survival or promoting antitumor responses in DLBCL. Consequently, the efficacy of standard-of-care and novel immunotherapies was determined using individual T-cell features. Furthermore, the experimental targeting of newly identified immune mechanisms has improved therapeutic responses in vivo. Our results elucidate that genetically driven LME landscapes influence therapeutic outcomes across distinct lymphoma subtypes, providing proof-of-concept for personalized treatment based on immune LME information.