Atypical memory B cells acquire Breg phenotypes in hepatocellular carcinoma

Atypical memory B cells acquire Breg phenotypes in hepatocellular carcinoma

JCI Insight

10.1172/jci.insight.187025

https://doi.org/10.1172/jci.insight.187025

Shi Yong Neo, Timothy Wai Ho Shuen, Shruti Khare, Joni Chong, Maichan Lau, Niranjan Shirgaonkar, Levene Chua, Junzhe Zhao, Keene Lee, Charmaine Tan, Rebecca Ba, Janice Lim, Joelle Chua, Hui Shi Cheong, Hui Min Chai, Chung Yip Chan, Alexander Yaw Fui Chung, Peng Chung Cheow, Prema Raj Jeyaraj, Jin Yao Teo, Ye Xin Koh, Aik Yong Chok, Pierce Kah Hoe Chow, Brian Goh, Wei Keat Wan, Wei Qiang Leow, Tracy Jie Zhen Loh, Po Yin Tang, Jayanthi Karunanithi, Nye Thane Ngo, Tony Kiat Hon Lim, Shengli Xu, Ramanuj DasGupta, Han Chong Toh, Kong-Peng Lam

25 February 2025

Neo, S. Y., Shuen, T. W. H., Khare, S., Chong, J., Lau, M., Shirgaonkar, N., Chua, L., Zhao, J., Lee, K., Tan, C., Ba, R., Lim, J., Chua, J., Cheong, H. S., Chai, H. M., Chan, C. Y., Chung, A. Y. F., Cheow, P. C., Jeyaraj, P. R., … Lam, K.-P. (2025). Atypical memory B cells acquire Breg phenotypes in hepatocellular carcinoma. JCI Insight, 10(7). https://doi.org/10.1172/jci.insight.187025

The functional plasticity of tumor-infiltrating lymphocyte B-cells (TIL-B) spans from antitumor responses to noncanonical immune suppression. Yet, how the tumor microenvironment (TME) influences TIL-B development is still underappreciated. Our current study integrated single-cell transcriptomics and B cell receptor (BCR) 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 and memory and naive 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, a nonswitched memory B cell subset acquired 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 that in turn, dampen T cell costimulation. To the best of our knowledge, these findings represent novel mechanisms of noncanonical 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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Research Foundation of Singapore - Competitive Research Programme
Grant Reference no. : NRF-CRP26-2021RS-0001

This research / project is supported by the National Medical Research Council - Open-Fund Large Collaborative Grant
Grant Reference no. : NMRC/OFLCG/003/2018

This research / project is supported by the National Medical Research Council - Open Fund - Individual Research Grant
Grant Reference no. : NMRC/OFIRG24jan-0111

This research is supported by core funding from: Singapore Immunology Network (A*STAR SIgN)
Grant Reference no. : NA

This research / project is supported by the National Research Foundation - SIS
Grant Reference no. : NRF2017_SISFP09

© 2025, Neo et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

https://oar.a-star.edu.sg/communities-collections/articles/22936

2379-3708

Singapore Immunology Network

https://insight.jci.org/articles/view/187025/version/2