T Cells Spatially Regulate B Cell Receptor Signaling in Lymphomas through H3K9me3 Modifications.

Abstract

Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is a subtype associated with poor survival outcomes. Despite identifying therapeutic targets through molecular characterization, targeted therapies have limited success. New strategies using immune-competent tissue models are needed to understand how DLBCL cells evade treatment. Here, synthetic hydrogel-based lymphoma organoids were used to demonstrate how signals in the lymphoid tumor microenvironment (Ly-TME) can alter B cell receptor (BCR) signaling and specific histone modifications, tri-methylation of histone 3 at lysine 9 (H3K9me3), dampening the effects of BCR pathway inhibition. Using imaging modalities, T cells increased DNA methyltransferase 3A expression and cytoskeleton formation in proximal ABC-DLCBL cells, regulated by H3K9me3. Expansion microscopy on lymphoma organoids revealed T cells increased the size and quantity of segregated H3K9me3 clusters in ABC-DLBCL cells. Our findings suggest re-organization of higher-order chromatin structures that may contribute to evasion or resistance to therapy via the emergence of novel transcriptional states. Treating ABC-DLBCL cells with a G9α histone methyltransferase inhibitor reversed T cell-mediated modulation of H3K9me3 and overcame T cell-mediated attenuation of treatment response to BCR pathway inhibition. This study emphasized the Ly-TME's role in altering DLBCL fate and suggests targeting aberrant signaling and microenvironmental cross-talk could benefit high-risk patients. This article is protected by copyright. All rights reserved.