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Strong CD8+ T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Aim

We investigated whether tumor-specific CD8+ T-cell responses affect tumor-free survival as well as the relationship between CD8+ T-cell responses against tumor-associated antigens (TAAs) and the clinical course after tumor treatment in patients with hepatocellular carcinoma (HCC).

Methods

Twenty patients with HCC that were treated by radiofrequency ablation or trans-catheter chemo-embolization (TACE) and in whom HCC was undetectable by ultrasonography, CT, and/or MRI 1 month after treatment were enrolled in the study. Before and after treatment for HCC, analyses of TAA (glypican-3, NY-ESO-1, and MAGE-1)-specific CD8+ T-cell responses were evaluated with an interferon-γ enzyme-linked immunospot (ELISpot) assay using peripheral CD8+ T-cells, monocytes, and 104 types of 20-mer synthetic peptide overlapping by 10 residues and spanning the entirety of the 3 TAAs.

Results

Sixteen out of 20 patients (80%) showed a positive response (≥10 TAA-specific cells/105 CD8+ T-cells) before or after treatment. When we performed univariate analysis of prognostic factors for the tumor-free period in the 20 patients, platelet count, prothrombin time, and the number of TAA-specific CD8+ T-cells after treatment were significant factors (P = 0.027, 0.030, and 0.004, respectively). In multivariate analysis, the magnitude of the TAA-specific CD8+ T-cell response (≥40 TAA-specific cells/105 CD8+ T-cells) was the only significant prognostic factor for a prolonged tumor-free interval (hazard ratio 0.342, P = 0.022).

Conclusions

Our results suggest that strong TAA-specific CD8+ T-cell responses suppress the recurrence of HCC. Immunotherapy to induce TAA-specific cytotoxic T lymphocytes by means such as the use of peptide vaccines should be considered for clinical application in patients with HCC after local therapy.

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References

  1. Palmer DH, Midgley RS, Mirza N, Torr EE, Ahmed F, Steele JC, et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology. 2009;49:124–32.

    Article  PubMed  Google Scholar 

  2. 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;28:496–504.

    Article  PubMed  Google Scholar 

  3. Chi KH, Liu SJ, Li CP, Kuo HP, Wang YS, Chao Y, et al. Combination of conformal radiotherapy and intratumoral injection of adoptive dendritic cell immunotherapy in refractory hepatoma. J Immunother. 2005;28:129–35.

    Article  PubMed  Google Scholar 

  4. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991;254:1643–7.

    Article  PubMed  Google Scholar 

  5. Suzuki K, Tsujitani S, Konishi I, Yamaguchi Y, Hirooka Y, Kaibara N. Expression of MAGE genes and survival in patients with hepatocellular carcinoma. Int J Oncol. 1999;15:1227–32.

    CAS  PubMed  Google Scholar 

  6. Tahara K, Mori M, Sadanaga N, Sakamoto Y, Kitano S, Makuuchi M. Expression of the MAGE gene family in human hepatocellular carcinoma. Cancer. 1999;85:1234–40.

    Article  CAS  PubMed  Google Scholar 

  7. Kariyama K, Higashi T, Kobayashi Y, Nouso K, Nakatsukasa H, Yamano T, et al. Expression of MAGE-1 and -3 genes and gene products in human hepatocellular carcinoma. Br J Cancer. 1999;81:1080–7.

    Article  CAS  PubMed  Google Scholar 

  8. Ueda Y, Shimizu K, Itoh T, Fuji N, Naito K, Shiozaki A, et al. Induction of peptide-specific immune response in patients with primary malignant melanoma of the esophagus after immunotherapy using dendritic cells pulsed with MAGE peptides. Jpn J Clin Oncol. 2007;37:140–5.

    Article  PubMed  Google Scholar 

  9. Chen YT, Scanlan MJ, Sahin U, Tureci O, Gure AO, Tsang S, et al. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci USA. 1997;94:1914–8.

    Article  CAS  PubMed  Google Scholar 

  10. Korangy F, Ormandy LA, Bleck JS, Klempnauer J, Wilkens L, Manns MP, et al. Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin Cancer Res. 2004;10:4332–41.

    Article  CAS  PubMed  Google Scholar 

  11. Chen CH, Chen GJ, Lee HS, Huang GT, Yang PM, Tsai LJ, et al. Expressions of cancer-testis antigens in human hepatocellular carcinomas. Cancer Lett. 2001;164:189–95.

    Article  CAS  PubMed  Google Scholar 

  12. Hsu HC, Cheng W, Lai PL. Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution. Cancer Res. 1997;57:5179–84.

    CAS  PubMed  Google Scholar 

  13. Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 2003;125:89–97.

    Article  CAS  PubMed  Google Scholar 

  14. Nakatsura T, Yoshitake Y, Senju S, Monji M, Komori H, Motomura Y, et al. Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker. Biochem Biophys Res Commun. 2003;306:16–25.

    Article  CAS  PubMed  Google Scholar 

  15. Hippo Y, Watanabe K, Watanabe A, Midorikawa Y, Yamamoto S, Ihara S, et al. Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma. Cancer Res. 2004;64:2418–23.

    Article  CAS  PubMed  Google Scholar 

  16. Shiina S, Teratani T, Obi S, Sato S, Tateishi R, Fujishima T, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology. 2005;129:122–30.

    Article  PubMed  Google Scholar 

  17. Doi H, Hiroishi K, Shimazaki T, Eguchi J, Baba T, Ito T, et al. Magnitude of CD8 T-cell responses against hepatitis C virus and severity of hepatitis do not necessarily determine outcomes in acute hepatitis C virus infection. Hepatol Res. 2009;39:256–65.

    Article  CAS  PubMed  Google Scholar 

  18. Akiyama Y, Maruyama K, Tai S, Komiyama M, Iizuka A, Takikawa M, et al. Characterization of a MAGE-1-derived HLA-A24 epitope-specific CTL line from a Japanese metastatic melanoma patient. Anticancer Res. 2009;29:647–55.

    CAS  PubMed  Google Scholar 

  19. Gnjatic S, Altorki NK, Tang DN, Tu SM, Kundra V, Ritter G, et al. NY-ESO-1 DNA vaccine induces T-cell responses that are suppressed by regulatory T cells. Clin Cancer Res. 2009;15:2130–9.

    Article  CAS  PubMed  Google Scholar 

  20. Motomura Y, Ikuta Y, Kuronuma T, Komori H, Ito M, Tsuchihara M, et al. HLA-A2 and -A24-restricted glypican-3-derived peptide vaccine induces specific CTLs: preclinical study using mice. Int J Oncol. 2008;32:985–90.

    CAS  PubMed  Google Scholar 

  21. Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature. 1998;392:86–9.

    Article  CAS  PubMed  Google Scholar 

  22. Onaitis M, Kalady MF, Pruitt S, Tyler DS. Dendritic cell gene therapy. Surg Oncol Clin N Am. 2002;11:645–60.

    Article  PubMed  Google Scholar 

  23. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52.

    Article  CAS  PubMed  Google Scholar 

  24. Gastl G, Plante M, Finstad CL, Wong GY, Federici MG, Bander NH, et al. High IL-6 levels in ascitic fluid correlate with reactive thrombocytosis in patients with epithelial ovarian cancer. Br J Haematol. 1993;83:433–41.

    Article  CAS  PubMed  Google Scholar 

  25. Hersh EM, Stopeck AT. Advances in the biological therapy and gene therapy of malignant disease. Clin Cancer Res. 1997;3:2623–9.

    CAS  PubMed  Google Scholar 

  26. Cormier JN, Panelli MC, Hackett JA, Bettinotti MP, Mixon A, Wunderlich J, et al. Natural variation of the expression of HLA and endogenous antigen modulates CTL recognition in an in vitro melanoma model. Int J Cancer. 1999;80:781–90.

    Article  CAS  PubMed  Google Scholar 

  27. Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F, et al. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer. Hepatology. 2000;32:228–32.

    Article  CAS  PubMed  Google Scholar 

  28. Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Yamazaki O, et al. Effects of long-term postoperative interferon-alpha therapy on intrahepatic recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. A randomized, controlled trial. Ann Intern Med. 2001;134:963–7.

    CAS  PubMed  Google Scholar 

  29. Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med. 1996;334:1561–7.

    Article  CAS  PubMed  Google Scholar 

  30. Muto Y, Moriwaki H, Saito A. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med. 1999;340:1046–7.

    Article  CAS  PubMed  Google Scholar 

  31. Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000;356:802–7.

    Article  CAS  PubMed  Google Scholar 

  32. Kaibori M, Ishizaki M, Saito T, Matsui K, Kwon AH, Kamiyama Y. Risk factors and outcome of early recurrence after resection of small hepatocellular carcinomas. Am J Surg. 2009;198:39–45.

    Google Scholar 

  33. Maeda T, Shimada M, Harimoto N, Tsujita E, Aishima S, Tanaka S, et al. Prognosis of early hepatocellular carcinoma after hepatic resection. Hepatogastroenterology. 2008;55:1428–32.

    PubMed  Google Scholar 

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Acknowledgments

This study was supported in part by a grant from the Ministry of Health, Labor and Welfare of Japan (Kazumasa Hiroishi, Michio Imawari); a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Kazumasa Hiroishi); and a grant for the High-Technology Research Center Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Michio Imawari).

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan

    Kazumasa Hiroishi, Junichi Eguchi, Toshiyuki Baba, Tomoe Shimazaki, Shigeaki Ishii, Ayako Hiraide, Masashi Sakaki, Hiroyoshi Doi, Shojiro Uozumi, Risa Omori, Takuya Matsumura, Tatsuro Yanagawa, Takayoshi Ito & Michio Imawari

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  1. Kazumasa Hiroishi
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  2. Junichi Eguchi
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  3. Toshiyuki Baba
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  14. Michio Imawari
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Correspondence to Michio Imawari.

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Hiroishi, K., Eguchi, J., Baba, T. et al. Strong CD8+ T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma. J Gastroenterol 45, 451–458 (2010). https://doi.org/10.1007/s00535-009-0155-2

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  • DOI: https://doi.org/10.1007/s00535-009-0155-2

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