From Bench to Bed: the Tumor Immune Microenvironment and Current Immunotherapeutic Strategies for Hepatocellular Carcinoma

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2019 Sep 11

PMID 31500650

Citations 220

Authors

Yaojie Fu

Shanshan Liu

Shan Zeng

Hong Shen

Affiliations

Soon will be listed here.

Abstract

Hepatocellular carcinoma (HCC) ranks the most common primary liver malignancy and the third leading cause of tumor-related mortality worldwide. Unfortunately, despite advances in HCC treatment, less than 40% of HCC patients are eligible for potentially curative therapies. Recently, cancer immunotherapy has emerged as one of the most promising approaches for cancer treatment. It has been proven therapeutically effective in many types of solid tumors, such as non-small cell lung cancer and melanoma. As an inflammation-associated tumor, it's well-evidenced that the immunosuppressive microenvironment of HCC can promote immune tolerance and evasion by various mechanisms. Triggering more vigorous HCC-specific immune response represents a novel strategy for its management. Pre-clinical and clinical investigations have revealed that various immunotherapies might extend current options for needed HCC treatment. In this review, we provide the recent progress on HCC immunology from both basic and clinical perspectives, and discuss potential advances and challenges of immunotherapy in HCC.

Citing Articles

A novel 5-differentially expressed gene (DEG) signature predicting the prognosis in patients with metastatic liver malignancies and the prognostic and therapeutic potential of SPP1.

Liu J, Yu Z, Liu Q, Dou C, Cao P, Xie X Int J Clin Oncol. 2025; .

PMID: 40014188 DOI: 10.1007/s10147-025-02723-3.

Proteomic meta-analysis unveils new frontiers for biomarkers research in pancreatic carcinoma.

Di Marco F, Cufaro M, Damiani V, Dufrusine B, Pizzinato E, Di Ferdinando F Oncogenesis. 2025; 14(1):3.

PMID: 39956821 PMC: 11830788. DOI: 10.1038/s41389-025-00547-4.

Gut microbiota and immune alteration in cancer development: implication for immunotherapy.

Lau H, Zhang X, Yu J eGastroenterology. 2025; 1(1):e100007.

PMID: 39944250 PMC: 11770436. DOI: 10.1136/egastro-2023-100007.

NUAK1 acts as a novel regulator of PD-L1 via activating GSK-3β/β-catenin pathway in hepatocellular carcinoma.

Yao C, Tao H, He J, Zhu F, Xie C, Cheng Y Mol Med. 2025; 31(1):38.

PMID: 39901136 PMC: 11789290. DOI: 10.1186/s10020-025-01088-7.

FLT3 is associated with dendritic cell infiltration, tertiary lymphoid structure construction, and predict response to checkpoint inhibitors immunotherapy in solid cancers.

Tang Y, Wang H, Zhang J, Yang C, Xu F, Song Y Sci Rep. 2025; 15(1):2477.

PMID: 39833282 PMC: 11747321. DOI: 10.1038/s41598-025-86185-7.

References

Latchman Y, Wood C, Chernova T, Chaudhary D, Borde M, Chernova I . PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001; 2(3):261-8. DOI: 10.1038/85330. View

Butterfield L, Ribas A, Meng W, Dissette V, Amarnani S, Vu H . T-cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res. 2003; 9(16 Pt 1):5902-8. View

Alisa A, Ives A, Pathan A, Navarrete C, Williams R, Bertoletti A . Analysis of CD4+ T-Cell responses to a novel alpha-fetoprotein-derived epitope in hepatocellular carcinoma patients. Clin Cancer Res. 2005; 11(18):6686-94. DOI: 10.1158/1078-0432.CCR-05-0382. View

Unitt E, Marshall A, Gelson W, Rushbrook S, Davies S, Vowler S . Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol. 2006; 45(2):246-53. DOI: 10.1016/j.jhep.2005.12.027. View

Butterfield L, Ribas A, Dissette V, Lee Y, Yang J, de la Rocha P . A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res. 2006; 12(9):2817-25. DOI: 10.1158/1078-0432.CCR-05-2856. View

Nakamura S, Nouso K, Noguchi Y, Higashi T, Ono T, Jungbluth A . Expression and immunogenicity of NY-ESO-1 in hepatocellular carcinoma. J Gastroenterol Hepatol. 2006; 21(8):1281-5. DOI: 10.1111/j.1440-1746.2006.04271.x. View

Jager E, Karbach J, Gnjatic S, Neumann A, Bender A, Valmori D . Recombinant vaccinia/fowlpox NY-ESO-1 vaccines induce both humoral and cellular NY-ESO-1-specific immune responses in cancer patients. Proc Natl Acad Sci U S A. 2006; 103(39):14453-8. PMC: 1570182. DOI: 10.1073/pnas.0606512103. View

Liu T, Kirn D . Systemic efficacy with oncolytic virus therapeutics: clinical proof-of-concept and future directions. Cancer Res. 2007; 67(2):429-32. DOI: 10.1158/0008-5472.CAN-06-2871. View

Cao D, Yang J, Dou K, Ma L, Teng Z . alpha-fetoprotein and interleukin-18 gene-modified dendritic cells effectively stimulate specific type-1 CD4- and CD8-mediated T-Cell response from hepatocellular carcinoma patients in Vitro. Hum Immunol. 2007; 68(5):334-41. DOI: 10.1016/j.humimm.2007.01.008. View

10.

Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B . Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007; 132(7):2328-39. DOI: 10.1053/j.gastro.2007.03.102. View

11.

Gao Q, Qiu S, Fan J, Zhou J, Wang X, Xiao Y . Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007; 25(18):2586-93. DOI: 10.1200/JCO.2006.09.4565. View

12.

Wang Y, Huang F, Cai H, Zhong S, Liu X, Tan W . Potent antitumor effect of TRAIL mediated by a novel adeno-associated viral vector targeting to telomerase activity for human hepatocellular carcinoma. J Gene Med. 2008; 10(5):518-26. DOI: 10.1002/jgm.1177. View

13.

Pan K, Wang H, Chen M, Zhang H, Weng D, Zhou J . Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2008; 134(11):1247-53. DOI: 10.1007/s00432-008-0395-1. View

14.

Greten T, Manns M, Korangy F . Immunotherapy of HCC. Rev Recent Clin Trials. 2008; 3(1):31-9. DOI: 10.2174/157488708783330549. View

15.

Hoechst B, Ormandy L, Ballmaier M, Lehner F, Kruger C, Manns M . A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology. 2008; 135(1):234-43. DOI: 10.1053/j.gastro.2008.03.020. View

16.

Park B, Taeho Hwang , Liu T, Sze D, Kim J, Kwon H . Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 2008; 9(6):533-42. DOI: 10.1016/S1470-2045(08)70107-4. View

17.

Gonzalez-Carmona M, Lukacs-Kornek V, Timmerman A, Shabani S, Kornek M, Vogt A . CD40ligand-expressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo. Hepatology. 2008; 48(1):157-68. DOI: 10.1002/hep.22296. View

18.

He L, Gu J, Tang W, Fan J, Wei N, Zou W . Significant antitumor activity of oncolytic adenovirus expressing human interferon-beta for hepatocellular carcinoma. J Gene Med. 2008; 10(9):983-92. DOI: 10.1002/jgm.1231. View

19.

Zhang C, Zhang J, Niu J, Zhou Z, Zhang J, Tian Z . Interleukin-12 improves cytotoxicity of natural killer cells via upregulated expression of NKG2D. Hum Immunol. 2008; 69(8):490-500. DOI: 10.1016/j.humimm.2008.06.004. View

20.

Palmer D, Midgley R, Mirza N, Torr E, Ahmed F, Steele J . A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology. 2008; 49(1):124-32. DOI: 10.1002/hep.22626. View