HMGB2 Drives Tumor Progression and Shapes the Immunosuppressive Microenvironment in Hepatocellular Carcinoma: Insights from Multi-omics Analysis

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Sep 9

PMID 39247201

Authors

Yan-Zhu Chen

Zhi-Shang Meng

Zuo-Lin Xiang

Affiliations

Soon will be listed here.

Abstract

Background: Hepatocellular carcinoma (HCC) poses a significant health burden globally, with high mortality rates despite various treatment options. Immunotherapy, particularly immune-checkpoint inhibitors (ICIs), has shown promise, but resistance and metastasis remain major challenges. Understanding the intricacies of the tumor microenvironment (TME) is imperative for optimizing HCC management strategies and enhancing patient prognosis.

Methods: This study employed a comprehensive approach integrating multi-omics approaches, including single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (Bulk RNA-seq), and validation in clinical samples using spatial transcriptomics (ST) and multiplex immunohistochemistry (mIHC). The analysis aimed to identify key factors influencing the immunosuppressive microenvironment associated with HCC metastasis and immunotherapy resistance.

Results: HMGB2 is significantly upregulated in HCC, a transitional subgroup associated with aggressive metastasis. Furthermore, HMGB2 expression positively correlates with an immunosuppressive microenvironment, particularly evident in exhausted T cells. Notably, HMGB2 expression correlated positively with immunosuppressive markers and poor prognosis in HCC patients across multiple cohorts. ST combined with mIHC validated the spatial expression patterns of HMGB2 within the TME, providing additional evidence of its role in HCC progression and immune evasion.

Conclusion: HMGB2 emerges as a critical player of HCC progression, metastasis, and immunosuppression. Its elevated expression correlates with aggressive tumor behavior and poor patient outcomes, suggesting its potential as both a therapeutic target and a prognostic indicator in HCC management.

Citing Articles

Single-Cell Sequencing: Genomic and Transcriptomic Approaches in Cancer Cell Biology.

Ortega-Batista A, Jaen-Alvarado Y, Moreno-Labrador D, Gomez N, Garcia G, Guerrero E Int J Mol Sci. 2025; 26(5).

PMID: 40076700 PMC: 11901077. DOI: 10.3390/ijms26052074.

References

Xue R, Zhang Q, Cao Q, Kong R, Xiang X, Liu H . Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature. 2022; 612(7938):141-147. DOI: 10.1038/s41586-022-05400-x. View

Ianevski A, Giri A, Aittokallio T . Fully-automated and ultra-fast cell-type identification using specific marker combinations from single-cell transcriptomic data. Nat Commun. 2022; 13(1):1246. PMC: 8913782. DOI: 10.1038/s41467-022-28803-w. View

Llovet J, Pinyol R, Yarchoan M, Singal A, Marron T, Schwartz M . Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma. Nat Rev Clin Oncol. 2024; 21(4):294-311. DOI: 10.1038/s41571-024-00868-0. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Hao Y, Stuart T, Kowalski M, Choudhary S, Hoffman P, Hartman A . Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat Biotechnol. 2023; 42(2):293-304. PMC: 10928517. DOI: 10.1038/s41587-023-01767-y. View

Singal A, Kanwal F, Llovet J . Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat Rev Clin Oncol. 2023; 20(12):864-884. DOI: 10.1038/s41571-023-00825-3. View

Wang D, Liu B, Zhang Z . Accelerating the understanding of cancer biology through the lens of genomics. Cell. 2023; 186(8):1755-1771. DOI: 10.1016/j.cell.2023.02.015. View

Meng Y, Zhao Q, Sang Y, Liao J, Ye F, Qu S . GPNMB Gal-3 hepatic parenchymal cells promote immunosuppression and hepatocellular carcinogenesis. EMBO J. 2023; 42(24):e114060. PMC: 10711661. DOI: 10.15252/embj.2023114060. View

He H, Chen S, Fan Z, Dong Y, Wang Y, Li S . Multi-dimensional single-cell characterization revealed suppressive immune microenvironment in AFP-positive hepatocellular carcinoma. Cell Discov. 2023; 9(1):60. PMC: 10279759. DOI: 10.1038/s41421-023-00563-x. View

10.

Lu Y, Yang A, Quan C, Pan Y, Zhang H, Li Y . A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma. Nat Commun. 2022; 13(1):4594. PMC: 9357016. DOI: 10.1038/s41467-022-32283-3. View

11.

Pinato D, Fulgenzi C, DAlessio A . Immunotherapy at all stages of hepatocellular carcinoma. Nat Med. 2024; 30(3):640-641. DOI: 10.1038/s41591-024-02828-8. View

12.

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

13.

Chen S, Liao C, Hu H, Liao J, Chen Z, Li S . Hypoxia-driven tumor stromal remodeling and immunosuppressive microenvironment in scirrhous HCC. Hepatology. 2023; 79(4):780-797. DOI: 10.1097/HEP.0000000000000599. View

14.

Zhang F, Li X, Tian W . Unsupervised Inference of Developmental Directions for Single Cells Using VECTOR. Cell Rep. 2020; 32(8):108069. DOI: 10.1016/j.celrep.2020.108069. View

15.

Elosua-Bayes M, Nieto P, Mereu E, Gut I, Heyn H . SPOTlight: seeded NMF regression to deconvolute spatial transcriptomics spots with single-cell transcriptomes. Nucleic Acids Res. 2021; 49(9):e50. PMC: 8136778. DOI: 10.1093/nar/gkab043. View

16.

Aran D, Looney A, Liu L, Wu E, Fong V, Hsu A . Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019; 20(2):163-172. PMC: 6340744. DOI: 10.1038/s41590-018-0276-y. View

17.

Starkova T, Polyanichko A, Tomilin A, Chikhirzhina E . Structure and Functions of HMGB2 Protein. Int J Mol Sci. 2023; 24(9). PMC: 10179549. DOI: 10.3390/ijms24098334. View

18.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

19.

Barkley D, Moncada R, Pour M, Liberman D, Dryg I, Werba G . Cancer cell states recur across tumor types and form specific interactions with the tumor microenvironment. Nat Genet. 2022; 54(8):1192-1201. PMC: 9886402. DOI: 10.1038/s41588-022-01141-9. View

20.

Huang M, He M, Guo Y, Li H, Shen S, Xie Y . The Influence of Immune Heterogeneity on the Effectiveness of Immune Checkpoint Inhibitors in Multifocal Hepatocellular Carcinomas. Clin Cancer Res. 2020; 26(18):4947-4957. DOI: 10.1158/1078-0432.CCR-19-3840. View