Immunosuppressive Tumor Microenvironment and Immunotherapy of Hepatocellular Carcinoma: Current Status and Prospectives

Overview

Journal J Hematol Oncol

Publisher Biomed Central

Specialties Hematology
Oncology

Date 2024 Apr 28

PMID 38679698

Authors

Ke-Yu Shen

Ying Zhu

Sun-Zhe Xie

Lun-Xiu Qin

Affiliations

Soon will be listed here.

Abstract

Hepatocellular carcinoma (HCC) is a major health concern worldwide, with limited therapeutic options and poor prognosis. In recent years, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. The combination treatments based on ICIs have been the major trend in this area. Recently, dual immune checkpoint blockade with durvalumab plus tremelimumab has also emerged as an effective treatment for advanced HCC. However, the majority of HCC patients obtain limited benefits. Understanding the immunological rationale and exploring novel ways to improve the efficacy of immunotherapy has drawn much attention. In this review, we summarize the latest progress in this area, the ongoing clinical trials of immune-based combination therapies, as well as novel immunotherapy strategies such as chimeric antigen receptor T cells, personalized neoantigen vaccines, oncolytic viruses, and bispecific antibodies.

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References

Fukumura D, Kloepper J, Amoozgar Z, Duda D, Jain R . Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018; 15(5):325-340. PMC: 5921900. DOI: 10.1038/nrclinonc.2018.29. View

Suthen S, Lim C, Nguyen P, Dutertre C, Lai H, Wasser M . Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC. Hepatology. 2022; 76(5):1329-1344. DOI: 10.1002/hep.32419. View

Heinrich B, Gertz E, Schaffer A, Craig A, Ruf B, Subramanyam V . The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma. Gut. 2021; 71(6):1161-1175. PMC: 8807808. DOI: 10.1136/gutjnl-2021-325288. View

Guo M, Liu M, Brooks D . Regulation and impact of tumor-specific CD4 T cells in cancer and immunotherapy. Trends Immunol. 2024; 45(4):303-313. DOI: 10.1016/j.it.2024.02.005. View

Batra S, Rathi P, Guo L, Courtney A, Fleurence J, Balzeau J . Glypican-3-Specific CAR T Cells Coexpressing IL15 and IL21 Have Superior Expansion and Antitumor Activity against Hepatocellular Carcinoma. Cancer Immunol Res. 2020; 8(3):309-320. PMC: 10765595. DOI: 10.1158/2326-6066.CIR-19-0293. View

Pan Z, Di S, Shi B, Jiang H, Shi Z, Liu Y . Increased antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1-CH3 fusion protein. Cancer Immunol Immunother. 2018; 67(10):1621-1634. PMC: 11028056. DOI: 10.1007/s00262-018-2221-1. View

Li Z, Pai R, Gupta S, Currenti J, Guo W, Di Bartolomeo A . Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy. Nat Cancer. 2024; 5(1):167-186. DOI: 10.1038/s43018-023-00672-2. View

Pavlovic N, Rani B, Gerwins P, Heindryckx F . Platelets as Key Factors in Hepatocellular Carcinoma. Cancers (Basel). 2019; 11(7). PMC: 6678690. DOI: 10.3390/cancers11071022. View

Ho D, Tsui Y, Chan L, Sze K, Zhang X, Cheu J . Single-cell RNA sequencing shows the immunosuppressive landscape and tumor heterogeneity of HBV-associated hepatocellular carcinoma. Nat Commun. 2021; 12(1):3684. PMC: 8211687. DOI: 10.1038/s41467-021-24010-1. View

10.

Wu M, Luo Z, Cai Z, Mao Q, Li Z, Li H . Spleen-targeted neoantigen DNA vaccine for personalized immunotherapy of hepatocellular carcinoma. EMBO Mol Med. 2023; 15(10):e16836. PMC: 10565630. DOI: 10.15252/emmm.202216836. View

11.

Garber K . China approves world's first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst. 2006; 98(5):298-300. DOI: 10.1093/jnci/djj111. View

12.

Zhang D, Lin Z, Wu M, Cai Z, Zheng Y, He L . Cytosolic Delivery of Thiolated Neoantigen Nano-Vaccine Combined with Immune Checkpoint Blockade to Boost Anti-Cancer T Cell Immunity. Adv Sci (Weinh). 2021; 8(6):2003504. PMC: 7967047. DOI: 10.1002/advs.202003504. View

13.

Pang N, Shi J, Qin L, Chen A, Tang Y, Yang H . IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. J Hematol Oncol. 2021; 14(1):118. PMC: 8323212. DOI: 10.1186/s13045-021-01128-9. View

14.

Lau W, Lai E . Salvage surgery following downstaging of unresectable hepatocellular carcinoma--a strategy to increase resectability. Ann Surg Oncol. 2007; 14(12):3301-9. DOI: 10.1245/s10434-007-9549-7. View

15.

Guo X, Tan S, Wang T, Sun R, Li S, Tian P . NAD + salvage governs mitochondrial metabolism, invigorating natural killer cell antitumor immunity. Hepatology. 2022; 78(2):468-485. DOI: 10.1002/hep.32658. View

16.

Rochigneux P, Chanez B, de Rauglaudre B, Mitry E, Chabannon C, Gilabert M . Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials. Cancers (Basel). 2021; 13(2). PMC: 7828372. DOI: 10.3390/cancers13020271. View

17.

Zhu G, Tang Z, Huang R, Qu W, Fang Y, Yang R . CD36 cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor. Cell Discov. 2023; 9(1):25. PMC: 9988869. DOI: 10.1038/s41421-023-00529-z. View

18.

Ma C, Fu Q, Diggs L, McVey J, McCallen J, Wabitsch S . Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD. Cancer Cell. 2022; 40(9):986-998.e5. PMC: 9474605. DOI: 10.1016/j.ccell.2022.08.004. View

19.

de Vries N, van Unen V, Ijsselsteijn M, Abdelaal T, van der Breggen R, Sarasqueta A . High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity. Gut. 2019; 69(4):691-703. PMC: 7063399. DOI: 10.1136/gutjnl-2019-318672. View

20.

Xu J, Shen J, Gu S, Zhang Y, Wu L, Wu J . Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial. Clin Cancer Res. 2020; 27(4):1003-1011. DOI: 10.1158/1078-0432.CCR-20-2571. View