T Cells Spatially Regulate B Cell Receptor Signaling in Lymphomas through H3K9me3 Modifications
Lucy S Britto1, Deepali Balasubramani1, Sona Desai1
1Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA.
Advanced Healthcare Materials
|June 5, 2024
Summary
Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cells evade treatment via tumor microenvironment signals. Targeting histone modifications and microenvironmental crosstalk may improve therapy for high-risk patients.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) has poor survival outcomes, and targeted therapies show limited efficacy.
- Understanding how DLBCL cells evade treatment requires advanced immune-competent models.
- The lymphoid tumor microenvironment (Ly-TME) plays a critical role in DLBCL progression and treatment resistance.
Purpose of the Study:
- To investigate how Ly-TME signals influence ABC-DLBCL cell behavior and treatment response.
- To explore the role of B cell receptor (BCR) signaling and histone modifications in therapy evasion.
- To identify novel therapeutic strategies targeting microenvironmental interactions.
Main Methods:
- Utilized synthetic hydrogel-based lymphoma organoids as immune-competent models.
- Employed imaging modalities and expansion microscopy to analyze cellular interactions and chromatin structures.
- Investigated the effects of BCR pathway inhibition and G9α histone methyltransferase inhibition.
Main Results:
- Ly-TME signals, particularly from T cells, alter BCR signaling and H3K9me3 (histone 3 tri-methylation at lysine 9) in ABC-DLBCL cells.
- T cells promote DNA methyltransferase 3A expression and cytoskeleton formation, regulated by H3K9me3.
- T cells induce larger and more numerous H3K9me3 clusters, suggesting higher-order chromatin reorganization contributing to therapy resistance.
- G9α inhibition reversed T cell-mediated H3K9me3 modulation and restored treatment response to BCR pathway inhibitors.
Conclusions:
- The Ly-TME significantly impacts DLBCL cell fate and therapy response by altering signaling pathways and chromatin organization.
- Aberrant signaling and microenvironmental crosstalk are critical mechanisms of treatment evasion in ABC-DLBCL.
- Targeting these microenvironmental interactions, potentially with G9α inhibitors, offers a promising strategy for high-risk DLBCL patients.
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