A Dual-Function DNA Vaccine Encoding Carcinoembryonic Antigen and CD40 Ligand Trimer Induces T Cell-Mediated Protective Immunity Against Colon Cancer in Carcinoembryonic Antigen-Transgenic Mice

Abstract

A carcinoembryonic Ag (CEA)-based DNA vaccine encoding both CEA and CD40 ligand trimer achieved effective tumor-protective immunity against murine colon carcinoma in CEA-transgenic mice by activating both naive T cells and dendritic cells. Peripheral T cell tolerance to CEA was broken in a prophylactic model by this novel, dual-function DNA vaccine, whose efficacy was further enhanced by boosts with a recombinant Ab-IL-2 fusion protein (huKS1/4-IL-2). These conclusions are supported by four lines of evidence. First, a lethal challenge of MC38-CEA-KS Ag murine colon carcinoma cells was for the first time completely rejected in 100% of experimental animals treated by oral gavage of this DNA vaccine carried by attenuated Salmonella typhimurium, followed by five boosts with huKS1/4-IL-2. Second, specific activation of dendritic cells was indicated by their marked up-regulation in expression of costimulatory molecules B7.1 (CD80), B7.2 (CD86), and ICAM-1. Third, a decisive increase over control values was observed in both MHC class I Ag-restricted cytotoxicity of CTLs from successfully vaccinated mice and secretion of proinflammatory cytokines IFN-γ and IL-12. Fourth, activation of CTLs was augmented, as indicated by up-regulation of activity markers LFA-1, CD25, CD28, and CD69. Taken together, these results suggest that a dual-function DNA vaccine encoding CEA and CD40 ligand trimer combined with tumor-targeted IL-2 may be a promising strategy for the rational development of DNA-based cancer vaccines for future clinical applications.

Cutting Edge: A Potent Adjuvant Effect of Ligand to Receptor Activator of NF-κB Gene for Inducing Antigen-Specific CD8+ T Cell Response by DNA and Viral Vector Vaccination

“…Considering the previous studies that demonstrated a potent adjuvant activity of the CD40L gene for inducing protective immunity against Leishmania major infection and tumors (9,10), our present results indicating no significant effects of pCD40L were somewhat unexpected. However, this discrepancy may be explained by a difference in the construction of CD40L used for those studies.…”

Incorporation of Glycosylphosphatidylinositol-Anchored Granulocyte- MacrophageColony-Stimulating Factor or CD40 Ligand Enhances Immunogenicity of Chimeric Simian Immunodeficiency Virus-Like Particles

“…As a result of the upregulation of costimulatory molecules (51,58), the APCs are activated, the CD4 ϩ -T-cell responses are augmented by increased cytokine production (10), and CD4-dependent naïve CD8 ϩ T cells are activated in vivo (44). Genetic fusion of CD40L to DNA vaccines was demonstrated to be effective in enhancing the cellular immune responses to a vaccine antigen (11,55).…”

Adjuvant Effect of the Propionibacterium acnes and Its Purified Soluble Polysaccharide on the Immunization with Plasmidial DNA Containing a Trypanosoma cruzi Gene

“…The association of specific adjuvants and DNA vaccination has been extensively investigated (11,21,25,37). Some studies demonstrated that co-administration of plasmids encoding cytokine genes as adjuvants significantly enhanced immune response.…”