Title:
Investigating the Effects of CD40-CD40 Ligand on Activated B Cell Diffuse Large B Cell Lymphoma B Cell Receptor Signaling
Investigating the Effects of CD40-CD40 Ligand on Activated B Cell Diffuse Large B Cell Lymphoma B Cell Receptor Signaling
Author(s)
Balasubramani, Deepali
Advisor(s)
Singh, Ankur
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Abstract
Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), one of the more aggressive forms of non-Hodgkin lymphoma, accounts for one-third of all DLBCL cases. There is an urgent need to develop new therapeutic interventions, as 40% of patients either relapse after an initial response or do not respond to current therapies. B cell lymphomas depend on and interact with lymphoid tumor microenvironment (Ly- TME) cues such as immune cells, stromal cells, and the extracellular matrix, that contributes to their pathogenesis. Understanding the biophysical and cellular components Ly-TME and its impact on ABC BCR signaling is thus necessary for developing therapeutic interventions to improve clinical outcomes for ABC DLBCL patients. We aim to investigate the effects of Ly-TME cues, specifically CD4+ T cell signaling via CD40-ligand (CD40L) and extracellular matrix (ECM) stiffness on ABC BCR signaling. We synthesized 2D cell cultures (2D model) and lymphoma organoids (3D model) encapsulated with DLBCLs, soluble CD40L, and anti-IgM and varied organoid stiffness as well as antigen/CD40L presentation in both models. We observed B cell spreading and filopodia formation in both models, with enhanced B cell spreading and filopodia formation in the 2D models where membrane-bound antigen – B cell encounter was recapitulated. CD40-CD40L engagement reduced actin expression and cell spreading in the stiffer organoids, and CD40 and IgM BCR expression increased with increasing stiffness. Finally, we observed a significant effect of Ly-TME stiffness on colocalization of IgM BCR with CD40 and Actin, suggesting potential involvement of the ECM in promoting integrin expression and stimulating mechanotransduction pathways to contribute to the colocalization.
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Date Issued
2022-05-03
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