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 Tamada

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)203-214
Number of pages12
JournalCancer Immunology, Immunotherapy
Volume61
Issue number2
DOIs
StatePublished - Feb 2012

Keywords

  • Co-stimulation
  • HVEM
  • T cell memory
  • Tumor immunity
  • scFv

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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