Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

Mechanism-directed combinational immunotherapies in liver cancer hold promise

Cellular & Molecular Immunology volume 20, pages 1395–1397 (2023)Cite this article

Subjects

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, and it is the third leading cause of cancer-related mortality worldwide. The primary causes of HCC include chronic infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) and alcoholic steatohepatitis (ASH) or nonalcoholic steatohepatitis (NASH). HCC exhibits significant intertumoral molecular heterogeneity, as evidenced by the absence of predominant oncogenic drivers. It also exhibits intratumor heterogeneity, particularly within the tumor microenvironment. Therapeutic options for advanced HCC remain limited. The standard treatments for unresectable HCC include locoregional therapies, systemic chemotherapies, radiation therapies, targeted therapies, and immune therapies.

Combining ICIs with other groups of anti-HCC agents presents another logical approach, as it can potentially deliver additive or synergistic effects. VEGF antagonists are a reasonable choice because VEGF is critical in immunosuppression. VEGF causes tumor vasculature abnormalities and directly affects immune cells [1]. In a phase 3 trial, the median progression-free survival for patients receiving the combination of atezolizumab + bevacizumab (anti-PD-L1 and anti-VEGF-A) was 6.8 months, and that for the sorafenib group was 4.3 months. Thus, this combination was approved in 2020. This marked a significant milestone, as it was the first time since the approval of sorafenib in 2007 that a new front-line treatment for HCC showed superior efficacy compared to existing options. Inspired by this advancement, considerable efforts are being undertaken to investigate additional combinations of ICIs with targeted therapies for HCC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Lee WS, Yang H, Chon HJ, Kim C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med. 2020;52:1475–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wu RY, Kong PF, Xia LP, Huang Y, Li ZL, Tang YY, et al. Regorafenib Promotes Antitumor Immunity via Inhibiting PD-L1 and IDO1 Expression in Melanoma. Clin Cancer Res : Off J Am Assoc Cancer Res. 2019;25:4530–41.

    Article  CAS  Google Scholar 

  3. Shigeta K, Matsui A, Kikuchi H, Klein S, Mamessier E, Chen IX, et al. Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma. J Immunother Cancer. 2020;8:e001435.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chuang HY, Chang YF, Liu RS, Hwang JJ. Serial low doses of sorafenib enhance therapeutic efficacy of adoptive T cell therapy in a murine model by improving tumor microenvironment. PloS ONE. 2014;9:e109992.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sprinzl MF, Puschnik A, Schlitter AM, Schad A, Ackermann K, Esposito I, et al. Sorafenib inhibits macrophage-induced growth of hepatoma cells by interference with insulin-like growth factor-1 secretion. J Hepatol. 2015;62:863–70.

    Article  CAS  PubMed  Google Scholar 

  6. Torrens L, Montironi C, Puigvehí M, Mesropian A, Leslie J, Haber PK, et al. Immunomodulatory Effects of Lenvatinib Plus Anti-Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma. Hepatol (Baltim, Md). 2021;74:2652–69.

    Article  CAS  Google Scholar 

  7. Esteban-Fabró R, Willoughby CE, Piqué-Gili M, Montironi C, Abril-Fornaguera J, Peix J, et al. Cabozantinib Enhances Anti-PD1 Activity and Elicits a Neutrophil-Based Immune Response in Hepatocellular Carcinoma. Clin Cancer Res : Off J Am Assoc Cancer Res. 2022;28:2449–60.

    Article  Google Scholar 

  8. Yu H, Shi T, Yao L, Xu D, Ding Y, Xia Q, et al. Elevated nuclear PIGL disrupts the cMyc/BRD4 axis and improves PD-1 blockade therapy by dampening tumor immune evasion. Cell Mol Immunol. 2023;20:867–80.

  9. Kelley RK, Rimassa L, Cheng AL, Kaseb A, Qin S, Zhu AX, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23:995–1008.

    Article  CAS  PubMed  Google Scholar 

  10. Finn RS, Kudo M, Merle P, Meyer T, Qin S, Ikeda M, et al. LBA34 Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2022;33:S1401.

    Article  Google Scholar 

Download references

Author contributions

G.M. and J.C. wrote the manuscript.

Funding

This work was supported by NJCCR fellowship COCR23PRF035 (to GM) and the National Cancer Institute grant R01CA272578 (to JC).

Author information

Authors and Affiliations

  1. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA

    Gregory Marshall & Jian Cao

  2. Department of Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901, USA

    Jian Cao

Authors
  1. Gregory Marshall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jian Cao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marshall, G., Cao, J. Mechanism-directed combinational immunotherapies in liver cancer hold promise. Cell Mol Immunol 20, 1395–1397 (2023). https://doi.org/10.1038/s41423-023-01068-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-023-01068-z

Search

Advanced search

Quick links