Abstract A012: USP11 links germinal center B-cell fate to adaptive immune crosstalk in immunized mice

Abstract Introduction: Germinal center B-cell responses require precise control of differentiation to balance plasma cell output and memory formation. Despite substantial insight into the transcriptional regulation of these processes, the role of post-translational control remains poorly understood. Disruption of B-cell developmental programs contributes to germinal center-derived lymphoid malignancies, and identifying these regulatory mechanisms is of significant clinical relevance. Ubiquitin Specific Peptidase 11 (USP11) has been implicated in lymphoid malignancies, including diffuse large B-cell lymphoma and T-cell acute lymphoblastic leukemia, and more recently in the survival of splenic marginal zone B cells. However, whether USP11 governs B-cell fate during physiological immune responses currently remains unknown. To address this gap, we used complementary B cell-specific conditional mouse models together with single-cell transcriptomic profiling to examine whether USP11 acts within B cells to control developmental pace and lineage choice upon immunization. Methods: Splenocytes from immunized USP11 loss-of-function, gain-of-function, and matched Cd19-Cre− control mice were profiled by 5′ scRNA-seq. Splenic B-cell states were defined using specific signature frameworks and orthogonally confirmed by multiplex immunohistochemistry. Integrated differential expression, enrichment, trajectory, pseudotime, and intercellular signaling analyses were then applied to evaluate cell-intrinsic and microenvironmental effects of USP11 perturbation. Results: USP11 altered transcriptional programs related to cellular metabolism, protein synthesis capacity, and cytokine response pathways. Loss of Usp11 accelerated the B-cell maturation axis and more robust terminally differentiated plasma states. By contrast, enforced USP11 expression restrained progression toward terminal differentiation and favored memory-skewed states. These B cell-intrinsic effects were accompanied by broader remodeling of the immune milieu, with USP11 overexpression favoring predicted B-T cell interaction networks and more differentiated T-cell states, whereas USP11 deficiency was linked to weaker co-stimulatory programs and a relative enrichment of less differentiated T-cell phenotypes. Conclusions: USP11 appears to shape germinal center output by influencing B-cell developmental trajectories and immune interactions within the splenic environment. These findings suggest a role for USP11-regulated programs in germinal center B cell biology and provide insight into processes associated with lymphoma development. Citation Format: Anirban Roychowdhury, Forum Kayastha, Mark A. Subler, Madelyn R. Lorenz, Won Sok. Lee, Nahid Nanaji, Jolene J. Windle, Bandish Kapadia, Ronald B. Gartenhaus. USP11 links germinal center B-cell fate to adaptive immune crosstalk in immunized mice [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A012.