Neoplastic CD3⁺ B cells remodel the DLBCL tumor microenvironment via single-cell and spatial transcriptomics

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with heterogeneous clinical outcomes.
• Understanding the cellular and molecular landscape of the DLBCL tumor microenvironment is crucial for developing effective therapies.

Purpose of the Study:

• To construct a high-resolution multi-omics map of DLBCL.
• To identify novel cellular subsets and their functional roles within the DLBCL microenvironment.
• To uncover molecular drivers and potential therapeutic targets for DLBCL.

Main Methods:

• Integration of single-cell, single-nucleus, and spatial transcriptomics.
• Identification and characterization of distinct cell populations within DLBCL tumors.
• Analysis of gene expression patterns and signaling pathways.
• Correlation of cellular features with clinical outcomes.

Main Results:

• Discovery of a recurrent, previously unrecognized subset of malignant B cells expressing CD3 (CD3⁺ B cells).
• Identification of a five-gene regulatory circuit (BCLAF1, CHURC1, FLI1, NFATC2, ELF2) driving the CD3⁺ B cell population.
• Association of CD3⁺ B cells with macrophage enrichment, M2 polarization, and TGF-β signaling.
• Correlation of CD3⁺ B cell abundance with advanced disease, poor treatment response, and reduced survival.

Conclusions:

• A CD3⁺ B cell subset with T cell-like features exists in DLBCL, contributing to an immunosuppressive tumor microenvironment.
• The FLI1 gene and the TGF-β axis are highlighted as potential therapeutic targets.
• This discovery provides new insights into DLBCL pathogenesis and offers avenues for targeted therapy development.