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


METHODS
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-X(L) and bcl-2 in CD4(+) and CD8(+) T cells in vaccinated mice.


CONCLUSIONS
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.
Kudo-Saito
Chie
C
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Hodge
James W
JW
Kwak
Heesun
H
Kim-Schulze
Seunghee
S
Schlom
Jeffrey
J
Kaufman
Howard L
HL
D053330:4-1BB Ligand; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018968:CD58 Antigens / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*; D014616:Vaccinia virus / Q000235:genetics*
D053330:4-1BB Ligand; D018122:B7-1 Antigen; D018968:CD58 Antigens; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; C505975:Tnfsf9 protein, mouse; D048069:Tumor Necrosis Factors; D018799:Intercellular Adhesion Molecule-1