Atypical memory B cells acquire Breg phenotypes in hepatocellular carcinoma

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Tumor-infiltrating lymphocyte B-cells (TIL-B) exhibit functional plasticity, contributing to both anti-tumor responses and immune suppression.
• The influence of the tumor microenvironment (TME) on TIL-B development remains underappreciated, particularly in hepatocellular carcinoma (HCC).

Purpose of the Study:

• To characterize TIL-B phenotypes and clonalities within the HCC TME.
• To investigate the mechanisms by which the HCC TME influences B cell function and contributes to immune suppression.

Main Methods:

• Integrated single-cell transcriptomics and B cell receptor (BCR) sequencing to profile TIL-B.
• Employed trajectory and gene regulatory network analysis to understand B cell differentiation pathways.
• Assessed the functional impact of HCC tumor cells on peripheral blood B cells.

Main Results:

• Identified distinct B cell populations (plasma, memory, naive) within the HCC TME.
• Revealed downregulation of BCR signaling in plasma cells and a subset of inflammatory memory B cells.
• Characterized a suppressive, age-associated B cell phenotype (TBET+CD11c+) expressing PD-L1, CD25, and granzyme B.
• Demonstrated that HCC tumor cells induce suppressive functions in peripheral B cells, dampening T cell costimulation.

Conclusions:

• Novel mechanisms of noncanonical immune suppression in HCC involving TIL-B were elucidated.
• Atypical memory B cells within the HCC TME and peripheral blood may function as regulatory B cells (Bregs).
• These findings highlight the critical role of B cells in shaping the immune landscape of HCC.