4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines

Chie Kudo-Saito, James W. Hodge, Heesun Kwak, Seunghee Kim-Schulze, Jeffrey Schlom, Howard L. Kaufman

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Purpose: Recombinant poxvirus vaccines have been explored as tumor vaccines. The immunogenicity of these vaccines can be enhanced by co-expressing costimulatory molecules and tumor-associated antigens. While the B7-CD28 interaction has been most comprehensively investigated, other costimulatory molecules utilize different signaling pathways and might provide further cooperation in T cell priming and survival. 4-1BB (CD137) is a TNF family member and is critical for activation and long-term maintenance of primed T cells. This study was conducted to determine if a poxvirus expressing the ligand for 4-1BB (4-1BBL) could further improve the immune and therapeutic responses of a previously reported poxvirus vaccine expressing a triad of costimulatory molecules (B7.1, ICAM-1, and LFA-3). Experimental design: A recombinant vaccinia virus expressing 4-1BBL was generated and characterized in an in vitro infection system. This vaccine was then used alone or in combination with a vaccinia virus expressing CEA, B7.1, ICAM-1, and LFA-3 in CEA-transgenic mice bearing established MC38 tumors. Tumor growth and immune responses against CEA and other tumor-associated antigens were determined. The level of anti-apoptotic proteins in responding T cells was determined by flow cytometry on tetramer selected T cells. Results: The combination of 4-1BBL with B7.1-based poxvirus vaccination resulted in significantly enhanced therapeutic effects against CEA-expressing tumors in a CEA-transgenic mouse model. This was associated with an increased level of CEA-specific CD4+ and CD8+ T cell responses, induction of antigen spreading to p53 and gp70, increased accumulation of CEA-specific T cells in the tumor microenvironment, and increased expression of bcl-XL and bcl-2 in CD4+ and CD8+ T cells in vaccinated mice. Conclusion: 4-1BBL cooperates with B7 in enhancing anti-tumor and immunologic responses in a recombinant poxvirus vaccine model. The inclusion of costimulatory molecules targeting distinct T cell signaling pathways provides a mechanism for enhancing the therapeutic effectiveness of tumor vaccines.

Original languageEnglish
Pages (from-to)4975-4986
Number of pages12
JournalVaccine
Volume24
Issue number23
DOIs
Publication statusPublished - 2006 Jun 5

Keywords

  • 4-1BBL
  • Cancer
  • Costimulation
  • Poxviruses
  • Vaccine

ASJC Scopus subject areas

  • Molecular Medicine
  • Immunology and Microbiology(all)
  • veterinary(all)
  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

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  • Cite this

    Kudo-Saito, C., Hodge, J. W., Kwak, H., Kim-Schulze, S., Schlom, J., & Kaufman, H. L. (2006). 4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines. Vaccine, 24(23), 4975-4986. https://doi.org/10.1016/j.vaccine.2006.03.042