1202 Unveiling Metabolic Vulnerabilities in Lupus B Cells: Targeting BCMA and Glucose Dependency for Therapeutic Strategies

Background Lupus is a complex autoimmune disease characterized by loss of self-tolerance, leading to dysregulated functions of T and B cells. Broadly increased glucose metabolism has been reported in many immune/inflammatory disorders, but little is known of its role in specific cell types during lupus pathogenesis. B-cell maturation antigen (BCMA) has been shown to be greatly upregulated in B cells in human SLE patients but has been primarily regarded in the context of a biomarker, with no therapeutic consideration. Current lupus treatments utilize broad-spectrum immunosuppressive agents, and targeted therapies are needed to effectively counteract this systemic autoimmune disorder. Investigating the metabolic profiles of lupus B cell subsets can offer insights into disease mechanisms and potential treatments. Objective We aimed to investigate the metabolic characteristics of germinal center B (GCB) cells in murine models of lupus, with a primary focus on elucidating their reliance on specific metabolic pathways. Moreover, we aimed to compare the metabolic differences between lupus BCMA+ and BCMA- GCB cells and those generated in response to foreign antigen immunization. Additionally, we sought to assess the therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, which specifically target BCMA+ B cells, in improving disease outcomes in lupus-prone mice. Methods The metabolic profiles of GCB cells were investigated in spontaneous murine models of lupus using Seahorse extracellular flux analysis, focusing on glycolysis and oxidative phosphorylation rates and mitochondrial fuel dependency. We also analyzed the glycolytic reliance in lupus BCMA+ and BCMA- GCB cells and those generated in response to foreign antigen immunization. To assess the efficacy of 2DG treatment in targeting GCB cells in vivo, flow cytometric analyses of cell viability and apoptosis were conducted in BXSB.Yaa lupus-prone mice. Furthermore, chimeric antigen receptor (CAR)-T cells expressing a proliferation inducing ligand (APRIL), a powerful ligand to BCMA, were designed to test the potential improvement of disease outcomes through the targeted removal of BCMA-expressing GCB cells. Results We found that GCB cells obtained from lupus-prone mice exhibited elevated levels of BCMA compared to those from immunized mice. Additionally, BCMA-expressing GCB cells also showed greater glucose uptake and glycolysis rate over BCMA- GCB cells. Notably, a differential dependency on glucose oxidation for survival between BCMA+ and BCMA- GCB cells was determined, rendering BCMA+ GCB cells highly susceptible to oxidative stress-induced apoptosis triggered by glycolysis inhibition via 2DG. Importantly, GCB cells from immunized mice showed no significant reliance on glycolysis, regardless of BCMA expression. Finally, the mortality of mice to lupus disease was significantly decreased upon the depletion of BCMA+ GCB cells through APRIL-based CAR-T therapy. Conclusions This study unveils differential metabolic requirements and vulnerabilities in GCB cells compared to immunization-induced GCB cells, with BCMA+ GCB cells from lupus mice showing heightened glucose oxidation dependency and susceptibility to glycolysis inhibition-induced apoptosis. Immunized GCB cells exhibit distinct metabolic characteristics and limited reliance on glycolysis, independent of BCMA expression. These findings shed light on the complex B cell metabolism in lupus, offering new insights for understanding lupus pathogenesis and developing innovative and targeted treatments, including transient 2DG exposure or APRIL-based CAR-T cell-based immunotherapy that effectively reduce lupus severity and prolong lifespan. Acknowledgments We thank the funding resources from JAX Director Initiative Fund, the DoD LRP Impact Award (HT9425–23-1–0308), the RILITE Foundation, and the John and Marcia Goldman Foundation. Lay summary We conducted a study to understand how the metabolism of certain immune cells, called B cells, is related to lupus. We focused on a protein called BCMA, which is found in higher levels on B cells from lupus patients. We discovered that BCMA+ B cells in lupus-prone mice have a higher dependence on glucose for survival, compared to BCMA- B cells. Interestingly, we found that B cells generated through immunization showed different metabolic characteristics and did not heavily rely on glucose metabolism, regardless of BCMA expression. Furthermore, targeting BCMA+ B cells using a specialized immune therapy reduced the risk of death in mice with lupus. These findings provide new insights into lupus disease and suggest potential avenues for developing treatments.