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