A mechanistic analysis of DNA vaccine-induced tumor immunity against the viral oncoprotein simian virus 40 large tumor antigen
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As cancer progresses toward the leading cause of death in the United States, biomedical research has become increasingly invested in the study of vaccines as potentiators of tumor immunity. Unlike current treatments for malignant disease, active immunotherapy has the potential to establish a specific, long-lasting anti-tumor response in the absence of debilitating side effects. In this study, we aim to characterize the immunological mechanisms of tumor immunity in BALB/c mice following vaccination with plasmid DNA, designated pCMV-Tag, that expresses as a transgene, a tumor specific antigen (Tag) from simian virus 40 (SV40). Briefly, BALB/c mice were immunized with pCMV-Tag or a control plasmid DNA preparation and subsequently challenged with a syngeneic murine fibroblast tumor cell line that expresses SV40 Tag in an experimental pulmonary metastasis model of malignant disease. Induction phase and effector phase-depletions of T lymphocytes and NK cells were performed in vivo to assess the relative importance of these cell types in the elicitation of tumor immunity. Additionally, gamma interferon (IFN-γ) neutralization experiments were conducted in vivo to examine the required activity of this cytokine at different stages of the immune response. An evaluation of anti-tumor immunity was carried out by monitoring the formation of lung tumor foci within the experimental pulmonary metastasis scenario followed by the evaluation of SV40 Tag specific immune responses. Our results indicate CD4+ T cells are critical mediators of the anti-tumor immune response, while CD8+ T cells and NK cells execute an important overlapping function within the immune effector phase. Studies of the specific cytokine environment show that vaccination with pCMV-Tag generates T cells that produce IFN-γ in vitro, which is a required component of the induction phase of the anti-tumor immune response. Of note, studies of the humoral immune response indicate that complete protection from tumor development precedes antibody production, and that the distribution of SV40 Tag-specific IgG sub-isotypes is consistent with a mixed Th1/Th2 immune response. Our findings provide insight into the general mechanisms of DNA vaccine-induced immunity against tumor-associated antigens, and have implications for the development of novel strategies to treat malignancies that express definable antigens that can be targeted through active vaccination.