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Cancer Immunology, Immunotherapy

, Volume 61, Issue 2, pp 203–214 | Cite as

Expression of anti-HVEM single-chain antibody on tumor cells induces tumor-specific immunity with long-term memory

  • Jang-June Park
  • Sudarshan Anand
  • Yuming Zhao
  • Yumiko Matsumura
  • Yukimi Sakoda
  • Atsuo Kuramasu
  • Scott E. Strome
  • Lieping Chen
  • Koji TamadaEmail author
Original article

Abstract

Genetic engineering of tumor cells to express immune-stimulatory molecules, including cytokines and co-stimulatory ligands, is a promising approach to generate highly efficient cancer vaccines. The co-signaling molecule, LIGHT, is particularly well suited for use in vaccine development as it delivers a potent co-stimulatory signal through the Herpes virus entry mediator (HVEM) receptor on T cells and facilitates tumor-specific T cell immunity. However, because LIGHT binds two additional receptors, lymphotoxin β receptor and Decoy receptor 3, there are significant concerns that tumor-associated LIGHT results in both unexpected adverse events and interference with the ability of the vaccine to enhance antitumor immunity. In order to overcome these problems, we generated tumor cells expressing the single-chain variable fragment (scFv) of anti-HVEM agonistic mAb on the cell surface. Tumor cells expressing anti-HVEM scFv induce a potent proliferation and cytokine production of co-cultured T cells. Inoculation of anti-HVEM scFv-expressing tumor results in a spontaneous tumor regression in CD4+ and CD8+ T cell-dependent fashion, associated with the induction of tumor-specific long-term memory. Stimulation of HVEM and 4-1BB co-stimulatory signals by anti-HVEM scFv-expressing tumor vaccine combined with anti-4-1BB mAb shows synergistic effects which achieve regression of pre-established tumor and T cell memory specific to parental tumor. Taken in concert, our data suggest that genetic engineering of tumor cells to selectively potentiate the HVEM signaling pathway is a promising antitumor vaccine therapy.

Keywords

HVEM Co-stimulation Tumor immunity scFv T cell memory 

Notes

Acknowledgments

We would like to thank Yingjia Liu and Amanda Miller for technical help in some experiments. This work was supported by ACGT Young Investigator Award and NIH grant HL088954 to K. T.

Conflict of interest

S.E.S. receives royalties through the Mayo Clinic College of Medicine for intellectual property related to B7-H1 and 4-1BB. He is also a co-founder and major stockholder in Gliknik Inc. a biotechnology company. The other authors have no financial conflict of interest.

Supplementary material

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Supplementary material 1 (TIFF 782 kb)
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Supplementary material 2 (TIFF 872 kb)
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Supplementary material 3 (TIFF 773 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jang-June Park
    • 1
  • Sudarshan Anand
    • 2
  • Yuming Zhao
    • 1
  • Yumiko Matsumura
    • 1
  • Yukimi Sakoda
    • 1
  • Atsuo Kuramasu
    • 3
  • Scott E. Strome
    • 1
    • 4
  • Lieping Chen
    • 5
  • Koji Tamada
    • 1
    • 3
    • 4
    Email author
  1. 1.Marlene and Stewart Greenebaum Cancer CenterUniversity of Maryland BaltimoreBaltimoreUSA
  2. 2.Department of Pathology and Moores UCSD Cancer CenterUniversity of CaliforniaSan DiegoUSA
  3. 3.Yamaguchi University Graduate School of MedicineUbeJapan
  4. 4.Department of Otorhinolaryngology-Head and Neck SurgeryUniversity of Maryland School of MedicineBaltimoreUSA
  5. 5.Department of ImmunologyYale University School of MedicineNew HavenUSA

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