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Vaccination with vascular progenitor cells derived from induced pluripotent stem cells elicits antitumor immunity targeting vascular and tumor cells

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Abstract

Vaccination of BALB/c mice with dendritic cells (DCs) loaded with the lysate of induced vascular progenitor (iVP) cells derived from murine-induced pluripotent stem (iPS) cells significantly suppressed the tumor of CMS-4 fibrosarcomas and prolonged the survival of CMS-4-inoculated mice. This prophylactic antitumor activity was more potent than that of immunization with DCs loaded with iPS cells or CMS-4 tumor cells. Tumors developed slowly in mice vaccinated with DCs loaded with iVP cells (DC/iVP) and exhibited a limited vascular bed. Immunohistochemistry and a tomato-lectin perfusion study demonstrated that the tumors that developed in the iVP-immunized mice showed a marked decrease in tumor vasculature. Immunization with DC/iVP induced a potent suppressive effect on vascular-rich CMS-4 tumors, a weaker effect on BNL tumors with moderate vasculature, and nearly no effect on C26 tumors with poor vasculature. Treatment of DC/iVP-immunized mice with a monoclonal antibody against CD4 or CD8, but not anti-asialo GM1, inhibited the antitumor activity. CD8+ T cells from DC/iVP-vaccinated mice showed significant cytotoxic activity against murine endothelial cells and CMS-4 cells, whereas CD8+ T cells from DC/iPS-vaccinated mice did not. DNA microarray analysis showed that the products of 29 vasculature-associated genes shared between genes upregulated by differentiation from iPS cells into iVP cells and genes shared by iVP cells and isolated Flk-1+ vascular cells in CMS-4 tumor tissue might be possible targets in the immune response. These results suggest that iVP cells from iPS cells could be used as a cancer vaccine targeting tumor vascular cells and tumor cells.

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Acknowledgments

This work was supported by Grant-in-Aid for Specific Research (C) and Grant-in-Aid for Challenging Exploratory Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the foundation of Cancer Research, Mitsui Life Social Welfare Foundation, Grant-in-Aid of the Japan Medical Association, and Takeda Science Foundation. The founders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan

    Shigeo Koido

  2. Department of Oncology, Institute of DNA Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan

    Shigeo Koido, Masaki Ito, Yukiko Sagawa, Kazumi Hayashi, Shin Kan, Yuko Kamata & Sadamu Homma

  3. Institute of Clinical Medicine and Research, Jikei University School of Medicine, Chiba, Japan

    Shigeo Koido

  4. Division of Cellular Signaling, Institute of Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan

    Masato Okamoto

  5. Division of Clinical Oncology/Hematology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan

    Kazumi Hayashi & Eijiro Nagasaki

  6. Shimbashi Medical Checkup Office, Jikei University Hospital, Tokyo, Japan

    Hideo Komita

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  1. Shigeo Koido
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  2. Masaki Ito
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Correspondence to Sadamu Homma.

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Koido, S., Ito, M., Sagawa, Y. et al. Vaccination with vascular progenitor cells derived from induced pluripotent stem cells elicits antitumor immunity targeting vascular and tumor cells. Cancer Immunol Immunother 63, 459–468 (2014). https://doi.org/10.1007/s00262-014-1531-1

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  • DOI: https://doi.org/10.1007/s00262-014-1531-1

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