Abstract:

The biology and clinical behavior of Diffuse Large B Cell Lymphoma (DLBCL) results from molecular alterations harbored by DLBCL cells and their interactions with the lymphoid tumor microenvironment (Ly-TME). Activated B cell (ABC) DLBCL, one of the more aggressive forms, depends on constitutive activation of nuclear factor κB (NF-κB) driven by B cell receptor (BCR), phosphoinositide 3-kinase (PI3K) and toll like receptor 9 (TLR9) pathways. Studies investigating disparities in lymphoma outcomes have identified African American patients with inferior 5-year overall survival, diagnosis age >10 years younger than other racial groups and distinct mutational profiles indicating different oncogenic mechanisms. We propose developing organoids that recapitulate the molecular and biophysical cues of the AA-ABC DLBCL Ly-TME to investigate differences in the molecular mechanisms driven by BCR signaling events and tumor-microenvironment interactions. Our hydrogel-based organoids will be composed of 4 arm Maleimide functionalized polyethylene glycol (PEG-4-MAL) with integrin binding peptides, crosslinked with degradable and nondegradable peptides, encapsulating growth factors that support AA - ABC DLBCL survival and proliferation. We further aim to investigate the impact of the Ly-TME on DLBCL progression, chronic BCR signaling events and response to single and combinatorial BCR targeted therapies.