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Dendritic cell-based vaccines suppress metastatic liver tumor via activation of local innate and acquired immunity

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Abstract

Background

Dendritic cell (DC)-based vaccines have been applied clinically in the setting of cancer, but tumor-associated antigens (TAAs) have not yet been enough identified in various cancers. In this study, we investigated whether preventive vaccination with unpulsed DCs or peptide-pulsed DCs could offer anti-tumor effects against MC38 or BL6 liver tumors.

Methods

Mice were subcutaneously (s.c.) immunized with unpulsed DCs or the recently defined TAA EphA2 derived peptide-pulsed dendritic cells (Eph-DCs) to treat EphA2-positive MC38 and EphA2-negative BL6 liver tumors. Liver mononuclear cells (LMNCs) from treated mice were subjected to 51Cr release assays against YAC-1 target cells. In some experiments, mice were injected with anti-CD8, anti-CD4 or anti-asialo GM1 antibody to deplete each lymphocyte subsets.

Results

Immunization with unpulsed DCs displayed comparable efficacy against both MC38 and BL6 liver tumors when compared with Eph-DCs. Both DC-based vaccines significantly augmented the cytotoxicity of LMNCs against YAC-1 cells. In vivo antibody depletion studies revealed that NK cells, as well as, CD4+ and CD8+ T cells play critical roles in the anti-tumor efficacy associated with either DC-based modality.

Tumor-specific cytotoxic T lymphocyte (CTL) activity was generally higher if mice had received Eph-DCs versus unpulsed DCs. Importantly, the mice that had been protected from MC38 liver tumor by either unpulsed DCs or Eph-DCs became resistant to s.c. MC38 rechallenge, but not to BL6 rechallenge.

Conclusions

These results demonstrate that unpulsed DC vaccines might serve as an effective therapy for treating metastatic liver tumor, for which TAA has not yet been identified.

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Abbreviations

DC:

Dendritic cell

Eph-DCs:

EphA2 derived peptide-pulsed dendritic cells

CTLs:

Cytotoxic T cell lymphocytes

s.c.:

Subcutaneously

SCID:

Severe combined immuno-deficiency

BM:

Bone marrow

GM-CSF:

Granulocyte/macrophage-colony stimulating factor

PBS:

Phosphate-buffered saline

LMNC:

Liver mononuclear cell

TAA:

Tumor-associated antigen

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Acknowledgments

The authors wish to thank Dr. Walter J. Storkus (The University of Pittsburgh) for careful review and comments provided during the preparation of this manuscript. This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a Grant-in-Aid for Research on Hepatitis and BSE from the Ministry of Health, Labor and Welfare of Japan [N.H.].

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Shinjiro Yamaguchi, Tomohide Tatsumi, Tetsuo Takehara, Akira Sasakawa, Hayato Hikita, Keisuke Kohga, Akio Uemura, Ryotaro Sakamori, Kazuyoshi Ohkawa & Norio Hayashi

  2. Medical Center for Translational Research, Osaka University Hospital, Osaka, 565-0871, Japan

    Tomohide Tatsumi

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  1. Shinjiro Yamaguchi
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  2. Tomohide Tatsumi
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  10. Norio Hayashi
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Corresponding author

Correspondence to Norio Hayashi.

Additional information

Shinjiro Yamaguchi and Tomohide Tatsumi contributed equally to this work.

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Yamaguchi, S., Tatsumi, T., Takehara, T. et al. Dendritic cell-based vaccines suppress metastatic liver tumor via activation of local innate and acquired immunity. Cancer Immunol Immunother 57, 1861–1869 (2008). https://doi.org/10.1007/s00262-008-0514-5

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  • DOI: https://doi.org/10.1007/s00262-008-0514-5

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