Abstract IA01: B cell checkpoints as regulators of tumor immunity and self-tolerance

B cells are increasingly recognized as key modulators of anti-tumor immunity, yet their dual roles in promoting cancer progression and maintaining immune tolerance remain incompletely understood. We identified a distinct subset of B cells expressing T cell immunoglobulin and mucin domain 1 (TIM-1) that functionally shapes both tumor immunity and autoimmunity. In murine melanoma models, TIM-1+ B cells progressively accumulate in tumor-draining lymph nodes and display a unique immunoregulatory phenotype, marked by co-expression of PD-1, TIGIT, LAG-3, and TIM-3. Conditional deletion of TIM-1 in B cells significantly reduced tumor burden and enhanced tumor-specific CD8+ T cell responses, mediated by increased type I interferon signaling and improved B cell-driven antigen presentation. Conversely, TIM-1 signaling is essential for immune tolerance. Aged mice with B cell-specific deletion of Tim-1 or Tigit spontaneously developed multi-organ autoimmunity, including central nervous system inflammation and paralysis. These findings position B cell checkpoint molecules such as TIM-1 at the intersection of immune activation and tolerance. Modulating this pathway, by either disrupting or activating TIM-1 signaling, could yield novel therapeutic opportunities in both cancer immunotherapy and autoimmune disease. Citation Format: Lloyd Bod. B cell checkpoints as regulators of tumor immunity and self-tolerance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr IA01.