Atypical memory B cells acquire Breg phenotypes in hepatocellular carcinoma

  • JCI Insight. 2025 Feb 25:e187025. doi: 10.1172/jci.insight.187025.
Shi Yong Neo  1 ,  Timothy Wai Ho Shuen  2 ,  Shruti Khare  3 ,  Joni Chong  1 ,  Maichan Lau  1 ,  Niranjan Shirgaonkar  3 ,  Levene Chua  1 ,  Junzhe Zhao  2 ,  Keene Lee  1 ,  Charmaine Tan  2 ,  Rebecca Ba  2 ,  Janice Lim  2 ,  Joelle Chua  2 ,  Hui Shi Cheong  2 ,  Hui Min Chai  2 ,  Chung Yip Chan  4 ,  Alexander Yaw Fui Chung  4 ,  Peng Chung Cheow  4 ,  Prema Raj Jeyaraj  4 ,  Jin Yao Teo  4 ,  Ye Xin Koh  4 ,  Aik Yong Chok  4 ,  Pierce Kah Hoe Chow  4 ,  Brian Goh  4 ,  Wei Keat Wan  5 ,  Wei Qiang Leow  5 ,  Tracy Jie Zhen Loh  5 ,  Po Yin Tang  5 ,  Jayanthi Karunanithi  5 ,  Nye Thane Ngo  5 ,  Tony Kiat Hon Lim  5 ,  Shengli Xu  1 ,  Ramanuj Dasgupta  3 ,  Han Chong Toh  2 ,  Kong-Peng Lam  1
Affiliations
  • 1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 2. Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
  • 3. Laboratory of Precision Oncology and Cancer Evolution, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 4. Department of Hepato-pancreato-biliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore.
  • 5. Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.
PMID: 39998891 DOI: 10.1172/jci.insight.187025
Abstract

The functional plasticity of tumor-infiltrating B (TIL-B) cells spans from anti-tumor responses to non-canonical immune suppression. Yet, how tumor microenvironment (TME) influences TIL-B development is still underappreciated. Our current study integrated single cell transcriptomics and BCR (B cell receptor) Sequencing to profile TIL-B phenotypes and clonalities in hepatocellular carcinoma (HCC). Using trajectory and gene regulatory network analysis, we were able to characterize plasma cells, memory and naïve B cells within the HCC TME and further revealed a downregulation of BCR-signaling genes in plasma cells and a subset of inflammatory TNF+ memory B cells. Within the TME, non-switch memory B cell subset acquires an age-associated B cell phenotype (TBET+, CD11c+) and expressed higher levels of PD-L1, CD25 and granzyme B. We further demonstrated that the presence of HCC tumor cells could confer suppressive functions on peripheral blood B cells which in turn, dampen T cell co-stimulation. To the best of our knowledge, these findings represent novel mechanisms of non-canonical immune suppression in HCC. While previous studies identified atypical memory B cells in chronic hepatitis and across several solid Cancer types, we further highlighted their potential role as regulatory B cells (Bregs) within both the TME and peripheral blood of HCC patients.

Keywords
Adaptive immunity; Hepatology; Immunology.
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