Advertisement

Roles of the Immune System in the Development and Progression of Hepatocellular Carcinoma

  • João Maurício
  • Helen ReevesEmail author
  • Caroline L. Wilson
Chapter

Abstract

Hepatocellular carcinoma (HCC) typically arises within a background of underlying chronic liver disease. Persistent inflammation is the key element underpinning its development, regardless of the underlying aetiology of chronic liver disease. Several immunological mechanisms can impact the HCC development and progression, as well as response to treatments. Furthermore, there is increasing hope that targeting the immune response itself can be exploited as a therapeutic strategy. Many patients develop antigen-specific adaptive immune responses; however, the background of the liver as a tolerogenic organ and the tumour cells foster an immunosuppressive niche that prevents antigen-mediated clearance of tumour cells. Inhibitory immune mechanisms, such as the presence of regulatory T cells, macrophages and neutrophils with a pro-tumour phenotype, release of anti-inflammatory factors and expression of inhibitory receptors (e.g., cytotoxic T-lymphocyte-associated protein 4 or programmed cell death 1 receptor), contribute for the maintenance of that immunosuppressive microenvironment. This review summarises the knowledge on the contribution of the different immune system elements towards tumour development and progression, as well as current immunotherapeutic approaches being explored in the field.

Keywords

Hepatocellular carcinoma Cirrhosis Inflammation Tumour microenvironment Cancer immunology Immunotherapy 

References

  1. 1.
    Marengo A, Rosso C, Bugianesi E. Liver cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med. 2016;67:103–17.PubMedCrossRefGoogle Scholar
  2. 2.
    Knudsen ES, Gopal P, Singal AG. The changing landscape of hepatocellular carcinoma: etiology, genetics, and therapy. Am J Pathol. 2014;184(3):574–83.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Stickel F. Alcoholic cirrhosis and hepatocellular carcinoma. Adv Exp Med Biol. 2015;815:113–30.PubMedCrossRefGoogle Scholar
  4. 4.
    Reeves HL, Zaki MY, Day CP. Hepatocellular carcinoma in obesity, type 2 diabetes, and NAFLD. Dig Dis Sci. 2016;61(5):1234–45.PubMedCrossRefGoogle Scholar
  5. 5.
    Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol. 2013;10(9):542–52.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Alison MR, Nicholson LJ, Lin WR. Chronic inflammation and hepatocellular carcinoma. Recent Results Cancer Res. 2011;185:135–48.PubMedCrossRefGoogle Scholar
  7. 7.
    Makarova-Rusher OV, Medina-Echeverz J, Duffy AG, Greten TF. The yin and yang of evasion and immune activation in HCC. J Hepatol. 2015;62(6):1420–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Obeid JM, Kunk PR, Zaydfudim VM, Bullock TN, Slingluff CL Jr, Rahma OE. Immunotherapy for hepatocellular carcinoma patients: is it ready for prime time? Cancer Immunol Immunother. 2017;67(2):161–74.PubMedCrossRefGoogle Scholar
  9. 9.
    Eggert T, Wolter K, Ji J, Ma C, Yevsa T, Klotz S, et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell. 2016;30(4):533–47.CrossRefGoogle Scholar
  10. 10.
    Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 2006;10(2):99–111.PubMedCrossRefGoogle Scholar
  11. 11.
    Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531(7593):253–7.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Finkin S, Yuan D, Stein I, Taniguchi K, Weber A, Unger K, et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol. 2015;16(12):1235–44.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Haybaeck J, Zeller N, Wolf MJ, Weber A, Wagner U, Kurrer MO, et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell. 2009;16(4):295–308.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Sagiv JY, Michaeli J, Assi S, Mishalian I, Kisos H, Levy L, et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 2015;10(4):562–73.PubMedCrossRefGoogle Scholar
  15. 15.
    Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer. 2016;16(7):431–46.PubMedCrossRefGoogle Scholar
  16. 16.
    Powell DR, Huttenlocher A. Neutrophils in the tumor microenvironment. Trends Immunol. 2016;37(1):41–52.PubMedCrossRefGoogle Scholar
  17. 17.
    Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell. 2009;16(3):183–94.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Wilson CL, Jurk D, Fullard N, Banks P, Page A, Luli S, et al. NFkappaB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nat Commun. 2015;6:6818.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Zhou SL, Zhou ZJ, Hu ZQ, Huang XW, Wang Z, Chen EB, et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology. 2016;150(7):1646–58 e17.PubMedCrossRefGoogle Scholar
  20. 20.
    Medina-Echeverz J, Eggert T, Han M, Greten TF. Hepatic myeloid-derived suppressor cells in cancer. Cancer Immunol Immunother. 2015;64(8):931–40.PubMedCrossRefGoogle Scholar
  21. 21.
    Li HQ, Han YM, Guo QL, Zhang MG, Cao XT. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol. 2009;182(1):240–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49–61.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Yan W, Liu X, Ma H, Zhang H, Song X, Gao L, et al. Tim-3 fosters HCC development by enhancing TGF-beta-mediated alternative activation of macrophages. Gut. 2015;64(10):1593–604.PubMedCrossRefGoogle Scholar
  24. 24.
    Butterfield LH, Ribas A, Meng WS, Dissette VB, Amarnani S, Vu HT, et al. 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.PubMedGoogle Scholar
  25. 25.
    Lee WC, Wang HC, Hung CF, Huang PF, Lia CR, Chen MF. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother. 2005;28(5):496–504.PubMedCrossRefGoogle Scholar
  26. 26.
    Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med. 2013;19(3):329–36.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Shimizu K, Kotera Y, Aruga A, Takeshita N, Katagiri S, Ariizumi SI, et al. Postoperative dendritic cell vaccine plus activated T-cell transfer improves the survival of patients with invasive hepatocellular carcinoma. Hum Vaccin Immunother. 2014;10(4):970–6.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, et al. Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg. 2012;255(1):8–17.PubMedCrossRefGoogle Scholar
  29. 29.
    Faivre SJ, Santoro A, Kelley RK, Merle P, Gane E, Douillard J-Y, et al. A phase 2 study of a novel transforming growth factor-beta (TGF-β1) receptor I kinase inhibitor, LY2157299 monohydrate (LY), in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2014;32(suppl 3):abstract LBA173.CrossRefGoogle Scholar
  30. 30.
    Sangro B, Gomez-Martin C, de la Mata M, Inarrairaegui M, Garralda E, Barrera P, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81–8.PubMedCrossRefGoogle Scholar
  31. 31.
    El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Sangro B, Crocenzi TS, Welling TH, Iñarrairaegui M, Prieto J, Fuertes C, et al. Phase I dose escalation study of nivolumab (Anti-PD-1; BMS-936558; ONO- 4538) in patients (pts) with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis. J Clin Oncol. 2013;31(suppl):abstr TPS3111.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • João Maurício
    • 1
  • Helen Reeves
    • 1
  • Caroline L. Wilson
    • 2
  1. 1.Northern Institute for Cancer ResearchNewcastle UniversityNewcastle upon TyneUK
  2. 2.Faculty of Medical Sciences, Institute of Cellular MedicineNewcastle UniversityNewcastle upon TyneUK

Personalised recommendations