Original Article

Cancer Immunology, Immunotherapy

, Volume 61, Issue 11, pp 2143-2152

Combining a peptide vaccine with oral ingestion of Lentinula edodes mycelia extract enhances anti-tumor activity in B16 melanoma-bearing mice

  • Kousuke TanakaAffiliated withCentral R & D Laboratory Kobayashi Pharmaceutical Co., Ltd. Email author 
  • , Satoru IshikawaAffiliated withCentral R & D Laboratory Kobayashi Pharmaceutical Co., Ltd.
  • , Yasunori MatsuiAffiliated withCentral R & D Laboratory Kobayashi Pharmaceutical Co., Ltd.
  • , Takashi KawanishiAffiliated withCentral R & D Laboratory Kobayashi Pharmaceutical Co., Ltd.
  • , Makoto TamesadaAffiliated withCentral R & D Laboratory Kobayashi Pharmaceutical Co., Ltd.
  • , Nanae HarashimaAffiliated withDepartment of Immunology, Shimane University Faculty of Medicine
  • , Mamoru HaradaAffiliated withDepartment of Immunology, Shimane University Faculty of Medicine

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Abstract

New anticancer vaccines must overcome regulatory T cell (Treg)-mediated immunosuppression. We previously reported that oral ingestion of Lentinula edodes mycelia (L.E.M.) extract restores melanoma-reactive T cells in melanoma-bearing mice via a mitigation of Treg-mediated immunosuppression. In this study, we investigated the effect of oral ingestion of the extract on peptide vaccine-induced anti-tumor activity. The day after subcutaneous inoculation in the footpad with B16 melanoma, mice were freely fed the extract and were vaccinated with a tyrosinase-related protein 2180–188 peptide. The peptide vaccine was repeated thrice weekly. Melanoma growth was significantly suppressed in mice treated with both the peptide vaccine and L.E.M. extract compared with mice treated with vaccine or extract alone, and the effect was CD8+ T cell-dependent. The combination therapy increased H-2Kb-restricted and B16 melanoma-reactive T cells in the draining lymph nodes and spleen. Flow cytometric and immunohistological analyses revealed that the combination therapy significantly decreased the percentage of Tregs in the draining lymph nodes and spleen of melanoma-bearing mice compared to treatment with vaccine or extract alone. Kinetic analyses of peptide-specific T cells and Tregs revealed that induction of peptide-specific T cells by the peptide vaccine alone was transient, but when combined with L.E.M. extract, it efficiently prolonged the duration of peptide-specific T cell induction without increasing the percentage of Tregs. These results indicate that combination therapy enhances peptide vaccine-induced anti-tumor activity due to attenuation of the increase in the percentage of Tregs in tumor-bearing hosts.

Keywords

Regulatory T cells Cytotoxic T-lymphocyte Immunotherapy Biological response modifier Melanoma Tumor peptide vaccine