Abstract 3792: Antigen and therapeutically relevant T cell molecular checkpoints control B cell heterogeneity and function to deliver anti-tumor immunity

Abstract B cells predict survival and treatment success across cancers. Yet, gaps in the known mechanisms that regulate B cell function in cancer imparts challenges for therapeutic utilization. In our lab’s studies of B cell responses to aggressive mouse solid tumors, we find that specific qualities of antigen and key signals from CD4+ T cells to B cells mediates the composition and function in B cell responses to tumors. Using mouse models to track antigen and antigen-specific B cells in tumor draining lymph nodes, we find that neoantigen solubility or being membrane bound along with the degree of BCR-antigen affinity shapes B cell mediated tumor control, heterogeneity, and the capacity for B cell mediated epitope spreading. Testing how B cell responses to antigen are shaped immunetherapy, we show that anti-PD1 and anti-CTLA4 therapies elicit CD4+ T cell IL21 and CD40Lg signals; ultimately mediating the composition of B cell subsets and function. Expanding on CD40 ligand function with translationally relevant CD40 agonists, which mimick CD4+ T cell CD40 ligand, we find that this checkpoint can elicit anti-tumor extrafollicular memory B cells that use CD86 signals to cause CD8+ T cells to become cytotoxic and mediate tumor control. Thus, our findings advance the understanding of how B cells are regulated and function to provide durable anti-tumor immune responses. Citation Format: Daniel P. Hollern. Antigen and therapeutically relevant T cell molecular checkpoints control B cell heterogeneity and function to deliver anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3792.