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PD-1hi Identifies a Novel Regulatory B-cell Population in Human Hepatoma That Promotes Disease Progression
Published version of a preprint
Abstract
UNLABELLED: B cells often constitute abundant cellular components in human tumors. Regulatory B cells that are functionally defined by their ability to produce IL10 downregulate inflammation and control T-cell immunity. Here, we identified a protumorigenic subset of B cells that constitutively expressed higher levels of programmed cell death-1 (PD-1) and constituted ∼10% of all B cells in advanced-stage hepatocellular carcinoma (HCC). These PD-1(hi) B cells exhibited a unique CD5(hi)CD24(-/+)CD27(hi/+)CD38(dim) phenotype different from the phenotype of conventional CD24(hi)CD38(hi) peripheral regulatory B cells. TLR4-mediated BCL6 upregulation was crucial for PD-1(hi) B-cell induction by HCC environmental factors, and that effect was abolished by IL4-elicited STAT6 phosphorylation. Importantly, upon encountering PD-L1(+) cells or undergoing PD-1 triggering, PD-1(hi) B cells acquired regulatory functions that suppressed tumor-specific T-cell immunity and promoted cancer growth via IL10 signals. Our findings provide significant new insights for human cancer immunosuppression and anticancer therapies regarding PD-1/PD-L1. SIGNIFICANCE: We identify a novel protumorigenic PD-1(hi) B-cell subset in human HCC that exhibits a phenotype distinct from that of peripheral regulatory B cells. TLR4-mediated BCL6 upregulation is critical for induction of PD-1(hi) B cells, which operate via IL10-dependent pathways upon interacting with PD-L1 to cause T-cell dysfunction and foster disease progression. Cancer Discov; 6(5); 546-59. ©2016 AACR.See related commentary by Ren et al., p. 477This article is highlighted in the In This Issue feature, p. 461.
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“Since other cell types (such as dendritic cells and B cells) can also be influenced by PD-1 signaling, inhibition of the PD-1/PD-L1 pathway may also have T cell-independent effects, whose impact on immune responses during checkpoint inhibitor therapy remain to be elucidated (36, 58).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [58]
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Metadata
- Authors
- Xiao, X., Lao, X.-M., Chen, M.-M., Liu, R.-X., Wei, Y., Ouyang, F.-Z., Chen, D.-P., Zhao, X.-Y., Zhao, Q., Li, X.-F., Liu, C.-L., Zheng, L., & Kuang, D.-M.
- Affiliations
- 1Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
- Sun Yat-sen University Cancer Center (CN)
- Sun Yat-sen University (CN)
- Venue
- Cancer Discovery
- Published
- 2016-05-01
- Volume
- 6
- Issue
- 5
- Pages
- 546-559
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2295125580
- Cited by
- 352
- References
- 46
- Citations by year
- 2026: 23 · 2025: 42 · 2024: 37 · 2023: 35 · 2022: 46 · 2021: 57 · 2020: 35 · 2019: 34 · 2018: 20 · 2017: 13 · 2016: 10
- FWCI
- 15.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81422036, 31470855, 81171982)
- Guangdong Natural Science Funds for Distinguished Young Scholars (S2013050014639)
- Doctoral Dissertation of PR China (201230)
- Fundamental Research Funds for the Central Universities (15lgjc09)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- regulatory B cells, hepatocellular carcinoma, PD-L1, TLR4, BCL6, IL-10, STAT6, tumor immunosuppression, T cell suppression, B-cell phenotype, cancer immunotherapy
- MeSH terms
- Animals, Disease Models, Animal, Flow Cytometry, Hepatitis B, Hepatitis C, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Neoplasm Staging, Phenotype, Protein Binding, Recurrence, Signal Transduction, Biomarkers, Gene Expression, Immunophenotyping, Cytokines, Lymphocytes, Tumor-Infiltrating, Disease Progression, Cell Line, Tumor, STAT6 Transcription Factor, Mice, Proto-Oncogene Proteins c-bcl-6, Immunomodulation, B-Lymphocytes, Regulatory, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Heterografts
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