Lymphoma Galectin-1 Expression Drives CD20 Immunotherapy Resistance

Abstract

Non-Hodgkin’s lymphoma is the most commonly diagnosed hematologic cancer of adults in the United States, with the vast majority deriving from malignant B lymphocytes that express cell surface CD20. CD20 immunotherapy (Rituximab) is widely used to treat Non-Hodgkin’s lymphoma, even though the initial effectiveness of Rituximab varies widely amongst patients and typically wanes over time. The mechanisms through which lymphomas initially resist or gain resistance to immunotherapy are not well-established. To address this, a preclinical mouse model system was developed to comprehensively identify lymphoma transcriptomic changes that confer resistance to CD20 immunotherapy. The collection of spontaneous primary and familial lymphomas revealed that sensitivity to CD20 immunotherapy was not regulated by differences in CD20 expression, prior exposure to CD20 immunotherapy, nor serial in vivo passage. An unbiased forward exome screen of these primary lymphomas was used to validate the utility of this expansive lymphoma cohort, which revealed that increased lymphoma galectin-1 expression strongly correlated with resistance to immunotherapy. Genetically induced lymphoma galectin-1 expression ablated antibody-dependent lymphoma phagocytosis in vitro and lymphoma sensitivity to CD20 immunotherapy in vivo. Human NHLs also express elevated galectin-1 compared with non-malignant lymphocytes, demonstrating the ability of this preclinical model system to identify molecular targets that could be relevant to human therapy. This study therefore established a powerful preclinical model system that permits the comprehensive identification of the dynamic lymphoma molecular network that drives resistance to immunotherapy.