Skip to main content

Advertisement

Log in

Changes of host immunity in relation to efficacy in liver cirrhosis patients with advanced hepatocellular carcinoma treated by intra-arterial chemotherapy

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

It is known that tumors develop mechanisms to escape from the immune system and to inhibit antitumor responses. The aim of this study was to retrospectively assess changes of host immunity in relation to efficacy in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) treated by combined intra-arterial chemotherapy.

Methods

Thirty-seven adult Japanese LC patients with aHCC were treated by intra-arterial combination chemotherapy. The control group was composed of 19 adult Japanese patients with chronic hepatitis C diagnosed by pathological examination of liver biopsy specimens. All control patients were stage 1 according to the fibrosis score of Desment.

Results

Ten of the 37 patients (group PR) showed a partial response and 17 of the 37 patients (group SD) showed stable disease, but 10 of the 37 patients (group PD) showed no response. There were no significant differences in the percentage of Th1 cells between any of the groups either before or after chemotherapy. The percentage of Th2 cells was significantly higher in group PD before and after chemotherapy than in the control group (P < 0.05 by Tukey’s test). Although there was no significant difference, the percentage of Th2 cells was higher in group SD than in group PR.

Conclusions

The percentage of Th2 cells increased in LC patients with aHCC as the efficacy of intra-arterial combination chemotherapy decreased. These results indicated that intra-arterial chemotherapy might be not useful for patients with aHCC, because it induces Th2 dominant host immunity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Okuda K, Fujimoto I, Hanai A, Urano Y (1987) Changing incidence of hepatocellular carcinoma in Japan. Cancer Res 47:4967–4972

    PubMed  CAS  Google Scholar 

  2. Landis SH, Murray T, Bolden S, Wingo PA (1998) Cancer statistics. CA Cancer J Clin 48:6–29

    Article  PubMed  CAS  Google Scholar 

  3. El-Serag HB, Mason AC (1999) Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340:745–750

    Article  PubMed  CAS  Google Scholar 

  4. Taylor-Robinson SD, Foster GR, Arora S, Hargreaves S, Thomas HC (1997) Increase in primary liver cancer in the UK 1979–1994. Lancet 350:1142–1143

    Article  PubMed  CAS  Google Scholar 

  5. Deuffic S, Poynard T, Buffat L, Valleron AJ (1998) Trends in primary liver cancer. Lancet 351:214–215

    Article  PubMed  CAS  Google Scholar 

  6. Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H, Nakajima Y, Ohnishi K (1985) Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 56:918–928

    Article  PubMed  CAS  Google Scholar 

  7. Nagasue N, Yukaya H, Hamada T, Hirose S, Kanashima R, Inokuchi K (1984) The natural history of hepatocellular carcinoma. A study of 100 untreated cases. Cancer 54:1461–1465

    Article  PubMed  CAS  Google Scholar 

  8. Ensminger W, Niederhuber J, Dakhil S, Thrall J, Wheeler R (1981) Totally implanted drug delivery system for hepatic arterial chemotherapy. Cancer Treat Rep 65:393

    PubMed  CAS  Google Scholar 

  9. Toyoda H, Nakano S, Kumada T, Takeda I, Sugiyama K, Osada T, Kiriyama S, Suga T, Takahashi M (1995) The efficacy of continuous local arterial infusion of 5-fluorouracil and cisplatin through an implanted reservoir for severe advanced hepatocellular carcinoma. Oncology 52:295–299

    Article  PubMed  CAS  Google Scholar 

  10. Murata K, Shiraki K, Kawakita T, Yamamoto N, Okano H, Nakamura M, Sakai T, Deguchi M, Ohmori S, Nakano T (2003) Low-dose chemotherapy of cisplatin and 5-fluorouracil or doxorubicin via implanted fusion port for unresectable hepatocellular carcinoma. Anticancer Res 3:1719–1722

    Google Scholar 

  11. Okuda K, Tanaka M, Shibata J, Ando E, Ogata T, Kinoshita H, Eriguchi N, Aoyagi S, Tanikawa K (1999) Hepatic arterial infusion chemotherapy with continuous low dose administration of cisplatin and 5-fluorouracil for multiple recurrence of hepatocellular carcinoma after surgical treatment. Oncol Rep 6:587–591

    PubMed  CAS  Google Scholar 

  12. Nagai H, Matsui T, Kanayama M, Momiyama K, Ikoma A, Okano N, Ikehara T, Matsumaru K, Watanabe M, Iida K, Ishii K, Sumino Y, Miki K (2007) Assessment of combined intra-arterial low-dose 5-fluorouracil, cisplatin, and leucovolin chemotherapy for patients with advanced hepatocellular carcinoma using the Japan integrated staging score. J Med Soc Toho 54:21–28

    Google Scholar 

  13. Nagai H, Kanayama M, Higami K, Momiyama K, Ikoma A, Okano N, Matsumaru K, Watanabe M, Ishii K, Sumino Y, Miki K (2007) Twenty-four hour intra-arterial infusion of 5-fluorouracil, cisplatin, and leucovorin is more effective than 6-hour infusion for advanced hepatocellular carcinoma. World J Gastroenterol 13(2):280–284

    PubMed  CAS  Google Scholar 

  14. Kobayashi M, Kobayashi H, Pollard RB, Suzuki F (1998) A pathogenic role of Th2 cells and their cytokine products on the pulmonary metastasis of murine B16 melanoma. J Immunol 160:5869–5873

    PubMed  CAS  Google Scholar 

  15. Zitvogel L, Mayordomo JI, Tjandrawan T, DeLeo AB, Clarke MR, Lotze MT, Storkus WJ (1996) Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J Exp Med 183:87–97

    Article  PubMed  CAS  Google Scholar 

  16. Hu H-M, Urba WJ, Fox BA (1998) Gene-modified tumor vaccine with therapeutic potential shifts tumor-specific T cell response from type 2 to a type 1 cytokine profile. J Immunol 161:3033

    PubMed  CAS  Google Scholar 

  17. Fukuzawa K, Takahashi K, Furuta K, Tagaya T, Ishikawa T, Wada K, Omoto Y, Koji T, Kakumu S (2001) Expression of Fas/Fas ligand and its involvement in infiltrating lymphocytes in hepatocellular carcinoma. J Gastroenterol 36:681–688

    Article  PubMed  CAS  Google Scholar 

  18. Yakirevich E, Lefel O, Sova Y, Stein A, Cohen O, Izhak OB, Resnick MB (2002) Activated status of tumour-infiltrating lymphocytes and apoptosis in testicular seminoma. J Pathol 196:67–75

    Article  PubMed  Google Scholar 

  19. Ikeguchi M, Oi K, Hirooka Y, Kaibara N (2004) CD8+ lymphocyte infiltration and apoptosis in hepatocellular carcinoma. Eur J Surg Oncol 30:53–57

    Article  PubMed  CAS  Google Scholar 

  20. Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562

    Article  PubMed  CAS  Google Scholar 

  21. Unitt E, Rushbrook SM, Marshall A, Davies S, Gibbs P, Morris LS, Coleman N, Alexander GJ (2005) Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 41:722–730

    Article  PubMed  CAS  Google Scholar 

  22. Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F (2005) Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 65:2457–2464

    Article  PubMed  CAS  Google Scholar 

  23. Yang XH, Yamagiwa S, Ichida T, Matsuda Y, Sugahara S, Watanabe H, Sato Y, Abo T, Horwitz DA, Aoyagi Y (2006) Increase of CD4+ CD25+ regulatory T cells in the liver of patients with hepatocellular carcinoma. J Hepatol 45:254–262

    Article  PubMed  CAS  Google Scholar 

  24. Nagai H, Miyaki D, Matsui T, Kanayama M, Higami K, Momiyama K, Ikehara T, Watanabe M, Sumino Y, Miki K (2008) Th1/Th2 balance: an important indicator of efficacy for intra-arterial chemotherapy. Cancer Chemother Pharmacol Feb 8. [Epub ahead of print]

  25. [25] Iwamiya T, Sawada S, and Ohta Y. Repeated arterial infusion chemotherapy for inoperable hepatocellular carcinoma using an implantable drug delivery system. Cancer Chemother Pharmacol 1994;33(Suppl):S134–S138

    Google Scholar 

  26. Shinohara M, Ishii K, Takamura N (2003) Long-term changes of peripheral blood CD4-positive T cell subsets (Th1, Th2) in chronic hepatitis C patients with a sustained response no response to IFN. Hepatol Res 27:260–265

    Article  PubMed  CAS  Google Scholar 

  27. Jung T, Schauer U, Heusser C, Neumann C, Rieger C (1993) Detection of intracellular cytokines by flow cytometry. J Immunol Methods 159:197–207

    Article  PubMed  CAS  Google Scholar 

  28. Kudo M, Chung H, Osaki Y (2003) Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for new staging system, the Japan Integrated Staging score (JIS score). J Gastroenterol 38:207–215

    Article  PubMed  Google Scholar 

  29. Gabrilovich D (2004) Mechanisms and functional significance of tumor-induced dendritic-cell defects. Nat Rev Immunol 4:941–952

    Article  PubMed  CAS  Google Scholar 

  30. Hoffmann TK, Muller-Berghaus J, Ferris RL, Johnson JT, Storkus WJ, Whiteside TL (2002) Alterations in the frequency of dendritic cell subsets in the peripheral circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 8:1787–1793

    PubMed  Google Scholar 

  31. Della Bella S, Gennaro M, Vaccari M, Ferraris C, Nicola S, Riva A et al (2003) Altered maturation of peripheral blood dendritic cells in patients with breast cancer. Br J Cancer 89:1463–1472

    Article  PubMed  CAS  Google Scholar 

  32. Gabrilovich DI, Corak J, Ciernik IF, Kavanaugh D, Carbone DP (1997) Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 3:483–490

    PubMed  CAS  Google Scholar 

  33. Ishida T, Oyama T, Carbone DP, Gabrilovich DI (1998) Defective function of langerhans cells in tumor-bearing animals is the results of defective maturation from hemopoietic progenitors. J Immunol 161:4842–4851

    PubMed  CAS  Google Scholar 

  34. Ormandy LA, Farber A, Cantz T, Petrykowska S, Wedemeyer H, Horning M et al (2006) Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma. World J Gastroenterol 12:3275–3282

    PubMed  CAS  Google Scholar 

  35. Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP (1999) Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res 5:2963–2970

    PubMed  CAS  Google Scholar 

  36. Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP (1998) Vascular endothelial growth factor inhibits the development of dendritic cell and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92:4150–4166

    PubMed  CAS  Google Scholar 

  37. Ohm JE, Shurin MR, Esche C, Lotze MT, Carbone DP, Gabrilovich DI (1999) Effect of vascular endothelial growth factor and FLT3 ligand on dendritic cell generation in vivo. J Immunol 163:3260–3268

    PubMed  CAS  Google Scholar 

  38. Menetrier-Caux C, Montmain G, Dieu MC, Bain C, Favrot MC, Caux C, Blay JY (1998) Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood 92:4778–4791

    PubMed  CAS  Google Scholar 

  39. Ratta M, Fagnoni F, Curti A, Vescovini R, Sansoni P, Fogli M, Oliviero B, Ferri E, Della Cuna GR, Tura S, Baccarani M, Lemoli RM (2002) Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood 100:230–237

    Article  PubMed  CAS  Google Scholar 

  40. Park SJ, Nakagawa T, Kitamura H, Atsumi T, Kamon H, Sawa S, Kamimura D, Ueda N, Iwakura Y, Ishihara K, Murakami M, Hirano T (2004) IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J Immunol 173:3844–3854

    PubMed  CAS  Google Scholar 

  41. Yang AS, Lattime EC (2003) Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses. Cancer Res 63:2150–2157

    PubMed  CAS  Google Scholar 

  42. Beissert S, Hosoi J, Grabbe S, Asahina A, Granstein RD (1995) IL-10 inhibits tumor antigen presentation by epidermal antigen-presenting cells. J Immunol 154:1280–1286

    PubMed  CAS  Google Scholar 

  43. Steinbrink K, Graulich E, Kubsch S, Knop J, Enk AH (2002) CD4(+) and CD8(+) anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood 99:2468–2476

    Article  PubMed  CAS  Google Scholar 

  44. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096–1103

    Article  PubMed  CAS  Google Scholar 

  45. Ferrara N, Gerber HP, LeCounter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  PubMed  CAS  Google Scholar 

  46. Korangy F, Ormandy LA, Bleck JS, Klempnauer J, Wilkens L, Manns MP, Greten TF (2004) Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin Cancer Res 10:4332–4341

    Article  PubMed  CAS  Google Scholar 

  47. Matsui T, Nagai H, Sumino Y, Miki K (2008) Relationship of peripheral blood CD4-positive T cells to carcinogenesis in patients with HCV-related chronic hepatitis and liver cirrhosis. Cancer Chemother Pharmacol 62:401–406

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hidenari Nagai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Momiyama, K., Nagai, H. & Sumino, Y. Changes of host immunity in relation to efficacy in liver cirrhosis patients with advanced hepatocellular carcinoma treated by intra-arterial chemotherapy. Cancer Chemother Pharmacol 64, 271–277 (2009). https://doi.org/10.1007/s00280-008-0866-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-008-0866-8

Keywords

Navigation