Induction of immune tolerance toward tumor-associated-antigens enables growth of human hepatoma in mice

Shigeru Tatebe, Hitoshi Unate, Frank A. Sinicrope, Takashi Sakatani, Kenji Sugamura, Masato Makino, Hisao Ito, Niramol Savaraj, Nobuaki Kaibara, M. Tien Kuo

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Adoptive transfer of immunity against hepatitis B surface antigen (HBsAg) was previously shown to facilitate suppression of experimental human hepatocellular carcinoma (HCC) expressing HBsAg in athymic mice. We have shown that oral tolerance induces antigen-specific immune suppression of HBsAg by feeding hepatitis B virus (HBV) antigens. In the present study we evaluated the effect of oral tolerance induction toward HBV or HCC antigens on the growth of experimental HCC-expressing HBsAg in mice. Tolerance induction was induced in mice by 5 oral feedings of I μg HBV antigens or HCC-extracted proteins (50 μg protein) before vaccination with recombinant HBsAg. Splenocytes (2 × 106) from these mice were transferred to sublethally irradiated athymic BALB/c mice previously transplanted subcutaneously with 107 human hepatoma Hep3B cells. Adoptive transfer of splenocytes immunized toward HBsAg prevented tumor growth. At 4 weeks after splenocyte transplantation, tumor volume and serum alpha-fetoprotein (AFP) levels in athymic mice transplanted with splenocytes immunized to HBsAg were undetectable as compared with 1,048 ± 738 mm3 and 2,500 ± 1,431 ng/ml in recipients of naïve splenocytes (p < 0.0001). Mice receiving splenocytes tolerized toward Hep3B cells, as manifested by reduced serum HBs antibody levels, reduced HBV-specific stimulation index and reduced HBV-specific-IFN-γ spot-forming cells, had early tumor growth evident by elevated AFP serum levels, weight loss and mortality, which were suppressed at 6 weeks. Mice transplanted with splenocytes tolerized toward HBV antigens did not have direct evidence of tumor growth. Induction of oral tolerance toward HCC-extracted proteins enabled transient tumor growth in this model. This effect was mediated through downregulation of the anti-HBV immune response.

Original languageEnglish (US)
Pages (from-to)52-57
Number of pages6
JournalInternational Journal of Cancer
Volume97
Issue number1
DOIs
StatePublished - Jan 1 2002

Keywords

  • Hepatitis B surface antigen (HBsAg)
  • Hepatitis B virus
  • Hepatocellular carcinoma
  • Oral tolerance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Tatebe, S., Unate, H., Sinicrope, F. A., Sakatani, T., Sugamura, K., Makino, M., Ito, H., Savaraj, N., Kaibara, N., & Kuo, M. T. (2002). Induction of immune tolerance toward tumor-associated-antigens enables growth of human hepatoma in mice. International Journal of Cancer, 97(1), 52-57. https://doi.org/10.1002/ijc.1576