The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
Innate and adaptive immune cells in the tumor microenvironment
Gajewski, T. F., Schreiber, H., & Fu, Y.-X. (2013) · Nature Immunology · doi:10.1038/ni.2703 · Cited by 4,148
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Biswas, S. K., & Mantovani, A. (2010) · Nature Immunology · doi:10.1038/ni.1937 · Cited by 3,840
Molecular mechanisms of T cell co-stimulation and co-inhibition
Chen, L., & Flies, D. B. (2013) · Nature Reviews Immunology · doi:10.1038/nri3405 · Cited by 3,114
Follicular Helper CD4 T Cells (T FH )
Crotty, S. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-031210-101400 · Cited by 2,738
Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice
Deng, L., Liang, H. L., Burnette, B., Beckett, M., Darga, T. E., Weichselbaum, R. R., & Fu, Y. (2014) · Journal of Clinical Investigation · doi:10.1172/jci67313 · Cited by 2,119
Inhibitory B7-family molecules in the tumour microenvironment
Zou, W., & Chen, L. (2008) · Nature Reviews Immunology · doi:10.1038/nri2326 · Cited by 1,608
Blair, P. A., Noreña, L. Y., Flores-Borja, F., Rawlings, D. J., Isenberg, D. A., Ehrenstein, M. R., & Mauri, C. (2010) · Immunity · doi:10.1016/j.immuni.2009.11.009 · Cited by 1,574
Llosa, N. J., Cruise, M., Tam, A., Wicks, E. C., Hechenbleikner, E. M., Taube, J. M., Blosser, R. L., Fan, H., Wang, H., Luber, B. S., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0863 · Cited by 1,487
Innate Immune Pattern Recognition: A Cell Biological Perspective
Brubaker, S. W., Bonham, K. S., Zanoni, I., & Kagan, J. C. (2015) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112240 · Cited by 1,475
Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity
Curiel, T. J., Wei, S., Dong, H., Alvarez, X., Cheng, P., Mottram, P., Krzysiek, R., Knutson, K. L., Daniel, B., Zimmermann, M. C., et al. (2003) · Nature Medicine · doi:10.1038/nm863 · Cited by 1,314
Cited by
Sorted by citations
Items 301–350 of 350
Guo, M., Lu, Z., & Xiong, Y. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2022.1048127 · Cited by 1
B10 cells: Development, phenotype, and function in cancer
Li, D., & Ma, Y. (2024) · Advances in Clinical and Experimental Medicine · doi:10.17219/acem/176378 · Cited by 2
Vizioli, G., Nicoletti, A., Daniela, F., Funaro, B., Verme, L. Z. D., Ponziani, F. R., Zocco, M. A., Gasbarrini, A., & Gabrielli, M. (2025) · Applied Sciences · doi:10.3390/app15052279 · Cited by 1
The role and mechanism of tumor-associated regulatory B cell
Wang, Z., Liu, R., & Chu, Y. (2025) · Chinese Science Bulletin (Chinese Version) · doi:10.1360/tb-2024-1397 · Cited by 1
Self-citationDoytcheva, K., Lager, A. M., & Venkataraman, G. (2021) · Journal of Hematopathology · doi:10.1007/s12308-021-00474-4 · Cited by 1
Varma, S. (2016) · Gastroenterology & Hepatology Open Access · doi:10.15406/ghoa.2016.05.00137
Immune Suppressor Mechanisms in HCC
Greten, T. F., & Korangy, F. (2017) · Springer eBooks · doi:10.1007/978-3-319-64958-0_8
Chae, Y. K., Bae, W. H., Jung, M., Kim, Y., Anker, J. F., Tamragouri, K., Matsangou, M., & Giles, F. J. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/641712
Immune Checkpoint Inhibitors: A Step forward in Cancer Management
Carratù, M. R., Potenza, M. A., Nacci, C., Rasmo, D. D., & Signorile, A. (2019) · Madridge Journal of Oncogenesis · doi:10.18689/mjo-1000112
The indoleamine 2,3 dioxygenase pathway drives intratumoral B cell maintenancePreprint
Johnson, B. A., Aragaki, A. K., Williams, D. M., Rogers, O. C., Mountain, J., Luo, L., Zhang, W., Xian, L., Feng, M., Chia, L., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.25.456776
Cancer-immunotherapy biomarkers in the tumor microenvironment
Togashi, Y. (2021) · Okayama Igakkai Zasshi (Journal of Okayama Medical Association) · doi:10.4044/joma.133.151
Hu, J., Huang, X., Wei, Q., Xiao, X., & Lü, Y.-P. (2022) · Research Square · doi:10.21203/rs.3.rs-1522879/v1
Self-citationTumor immunology and the application of immunotherapy in ovarian carcinoma
Paijens, S. T. (2021) · University of Groningen research database (University of Groningen / Centre for Information Technology) · doi:10.33612/diss.182133606
Immunology: Principles and Applications
Alkhatib, A. J. (2022) · Springer eBooks · doi:10.1007/978-981-19-1162-0_1
Translational Research in Cancer Immunotherapies
Nishi, T., & Togashi, Y. (2022) · Haigan · doi:10.2482/haigan.62.363
Regulatory Cell Subset Responses in Cancerous Diseases: Pathophysiological and Clinical Challenges
Tsiogkas, S. G., Dardiotis, E., Rigopoulou, E. I., & Bogdanos, D. P. (2022) · Springer eBooks · doi:10.1007/978-3-030-80962-1_7-1
Research progress on mechanisms and predictive biomarkers for immune-related adverse eventsPreprint
Zhang, Y., Qu, Z., Zhang, T., Zhao, Z., Zhang, Y., & Gu, K. (2023) · Research Square · doi:10.21203/rs.3.rs-2494743/v1
Lin, C.-H., Elkholy, K. H., Wani, N. A., Ding, L., Hu, P. C., Barajas, J. M., Yu, L., Zhang, X., Jacob, S. T., Khan, W. N., et al. (2023) · doi:10.1158/1535-7163.c.6538365.v1
Zhao, S., Xiong, H., Hou, F., Zhang, Y., Kang, Q., & Sun, L. (2023) · Research Square · doi:10.21203/rs.3.rs-3228422/v1
Chemotherapy tips the scale in favour of cancer‐fighting B cells
Rui, K., Xiao, F., Tian, J., Chen, J., & Lu, L. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1407
Khlaiphuengsin, A., Tangkijvanich, P., & Hirankarn, N. (2018) · Chula Digiverse · doi:10.58837/chula.the.2018.339
B Cells and Antibody Production in Cancer
Duarte, J. D. G., Tavancheh, E., Quigley, L. T., Ostrouska, S., & Behren, A. (2023) · Springer eBooks · doi:10.1007/978-3-030-80962-1_4-1
CMTM6 maintains B cell-intrinsic CD40 expression to regulate anti-tumor immunityPreprint
Long, Y., Chen, R., Chang, W., Li, F., Gu, L., Sun, J., Chen, J., & Gong, L. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.05.583639
34-parameter full spectrum immunophenotyping panel of human regulatory and effector lymphocytesPreprint
Georgieva, Z. G., Coppard, V., Yang, J. H. M., Grenfell, R., & Jones, J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.21.585958
Recent Advances in Immune-based Therapy for Hepatocellular Carcinoma
Park, K. W., Park, T. H., Jang, E. J., & Sung, P. S. (2024) · Journal of Digestive Cancer Research · doi:10.52927/jdcr.2024.12.2.115
Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients
Cao, W.-H., Zhang, Y., Li, X.-X., Zhang, Z., & Li, M. (2024) · World Journal of Hepatology · doi:10.4254/wjh.v16.i10.1338
Self-citation苗, 舜. (2025) · Advances in Clinical Medicine · doi:10.12677/acm.2025.1551481
B cell-mediated immune tolerance and cancer immune evasion
Ren, D., & Li, Y. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-14064-8.00045-x
Cancer-Promoting Roles of B Cells
Biragyn, A., Chen, C., & Bodogai, M. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00188-5
Chronic inflammation induced immunosuppression
Greten, F. R., & Pesic, M. H. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-14064-8.00048-5
B Cells and Antibody Production in Cancer
Duarte, J. D. G., Tavancheh, E., Quigley, L. T., Ostrouska, S., & Behren, A. (2025) · Springer eBooks · doi:10.1007/978-3-032-00749-0_4
Regulatory Cell Subset Responses in Cancerous Diseases: Pathophysiological and Clinical Challenges
Tsiogkas, S. G., Dardiotis, E., Rigopoulou, E. I., & Bogdanos, D. P. (2025) · Springer eBooks · doi:10.1007/978-3-032-00749-0_7
Fernández-González, M., Llorente, S., Galián, J. A., Botella, C., González-López, R., Alegría, M. J., Hita, A., Moya‐Quiles, M. R., Martínez‐Banaclocha, H., Muro-Pérez, M., et al. (2025) · Antibodies · doi:10.3390/antib14040095
Chen, P., Chin, Y., & Chu, C.-Y. (2025) · 童綜合醫學雜誌 · doi:10.4103/etmj.etmj-d-25-00009
Qin, Y., Peng, F., 艾利莎, Mu, S., Li, Y., Yang, C., & Hu, Y. (2021) · Figshare · doi:10.6084/m9.figshare.14775736
HPV-dependent divergence of B cell immunity in head and neck squamous cell carcinoma
Li, X., Zhao, T., Li, Y., Zhong, Q., & An, Z. (2026) · Journal of Advanced Research · doi:10.1016/j.jare.2026.03.010
Self-citationChampiat, S. (2019) · theses.fr (ABES) · doi:10.70675/e358773dz1898z4feezbb3bzbdee7c7f20a6
Mapping the immune microenvironment of non-small cell lung cancer
Ge, X., Cai, M., Nie, J., Wang, L., Li, Y., Hu, Y., Meng, J., Liu, H., Geng, L., 花宝金, et al. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2026.105335
Self-citationHepatocellular Carcinoma – from Immunobiology to Immunotherapy
Roehlen, N., Bengsch, B., Rennert, C., Schultheiß, M., & Thimme, R. (2026) · TumorDiagnostik & Therapie · doi:10.1055/a-2851-6473
Orthotopic murine model of hepatocellular carcinoma
Silva, L., Repáraz, D., & Ruiz, M. (2026) · Methods in cell biology · doi:10.1016/bs.mcb.2026.06.003
The Dual Roles of Regulatory B Cells in Infection, Cancer, and Immunity
Feng, A., Li, Q., Jiang, N., & Chen, Q. (2026) · MedComm · doi:10.1002/mco2.70850
CMTM6 maintains B cell-intrinsic membrane CD40 stability to regulate anti-tumor immunity
Chen, R.-Q., Chang, W., Li, F., Gu, L., Chen, C., Zhang, R., Li, Z., Sun, J., Chen, J., Gong, L., et al. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.07.017
Bai, H., Fan, G., Deng, B., Liu, Y., Zhang, P., Cao, X., & Li, Y. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.117306
Shen, Z., Li, Z., Hu, X., Liu, T., & Yin, R. H. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102447
B cells in cancer: functions, mechanisms and therapeutic advances
Zhang, H., Cheng, K., Mo, J., Chen, M., Zhou, Z., Wang, Z., Yang, Z., Chen, X., & Zhang, W. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02811-4 · Cited by 1
Self-citationWang, Y., Che, X., Hu, X., & Feng, M. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2026.105626
Adilkhankyzy, A., Alpysbayeva, K., Тлеубергенов, Х., Nurmanov, B., Найманова, Б., Шисенбаева, Н., Agabek, A. B., Ташигул, Н., Seitzhan, A. M., Дуйсембеков, Б. А., et al. (2026) · Insects · doi:10.3390/insects17101033
Hassel, J. C., Machiraju, D., Winkler, J. K., Floßdorf, M., Richter, J., Lauenstein, C., Appel, L. M., Halama, N., Mughal, S. S., Brors, B., et al. (2026) · Life · doi:10.3390/life16111773
The pro-metastatic effect and mechanism of immune cells in tumor metastasis
Geng, S., Liang, H., Lu, K., Deng, C., Bao, D., & Xu, H. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.2007187
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
