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
Externally publishedYes

Fingerprint

4-1BB Ligand
Poxviridae
Immunity
Vaccines
immunity
vaccines
T-lymphocytes
T-Lymphocytes
neoplasms
Neoplasms
CD58 Antigens
Cancer Vaccines
Synthetic Vaccines
Vaccinia virus
Neoplasm Antigens
Intercellular Adhesion Molecule-1
Transgenic Mice
antigens
therapeutics
immune response

Keywords

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

ASJC Scopus subject areas

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

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

4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines. / Kudo-Saito, Chie; Hodge, James W.; Kwak, Heesun; Kim-Schulze, Seunghee; Schlom, Jeffrey; Kaufman, Howard L.

In: Vaccine, Vol. 24, No. 23, 05.06.2006, p. 4975-4986.

Research output: Contribution to journalArticle

Kudo-Saito, C, Hodge, JW, Kwak, H, Kim-Schulze, S, Schlom, J & Kaufman, HL 2006, '4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines', Vaccine, vol. 24, no. 23, pp. 4975-4986. https://doi.org/10.1016/j.vaccine.2006.03.042
Kudo-Saito C, Hodge JW, Kwak H, Kim-Schulze S, Schlom J, Kaufman HL. 4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines. Vaccine. 2006 Jun 5;24(23):4975-4986. https://doi.org/10.1016/j.vaccine.2006.03.042
Kudo-Saito, Chie ; Hodge, James W. ; Kwak, Heesun ; Kim-Schulze, Seunghee ; Schlom, Jeffrey ; Kaufman, Howard L. / 4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines. In: Vaccine. 2006 ; Vol. 24, No. 23. pp. 4975-4986.
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AU - Schlom, Jeffrey

AU - Kaufman, Howard L.

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N2 - 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.

AB - 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.

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