The role of broad-based immunity against the viral oncoprotein simian virus 40 large tumor antigen



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Immunotherapy represents a promising strategy for terminal cancers, such as malignant pleural mesothelioma (MPM), over the standard ineffective protocols of surgery, chemotherapy, and radiation. Our laboratory has defined the protective immunologic-based anti-tumor mechanisms in a murine experimental pulmonary metastasis model against the human cancer associated viral oncoprotein, Simian virus 40 (SV40) large tumor antigen (Tag). Systemic protection from tumorigenic growth initially requires the generation of SV40 Tag specific antibody when animals are prophylactically immunized with plasmid DNA or recombinant protein SV40 Tag vaccines. With regard to the adaptive immune phase, studies in Fc gamma receptor deficient and NK cell depleted wild type mice have demonstrated that recombinant SV40 Tag protein immunization and the ensuing SV40 Tag specific antibody response engages natural killer (NK) cell-dependent antibody-dependent cell-mediated cytotoxicity (ADCC) against tumor cells. Th1 ELISA and flow cytometry methods as well as T cell subset in vivo depletion schemes in the effector immune phase have indicated that upon lysis of neoplastic growth through ADCC, antigen presenting cells cross-present tumor antigens and cross-prime CD8+ T cells to initiate tumor killing through cytotoxic T lymphocyte (CTL) mechanisms. The characterization of this latter response is unique in that ADCC promoting CTL activity has not been previously described for a viral oncoprotein within the setting of cancer. We have also recently uncovered a required role of the innate immune phase upon experimental pulmonary tumor inoculation. In particular to NK cells, the abrogation of their function in vivo through antibody depletion leads to increased tumor nodules relative to unprotected challenged mice. NK cell activation either in vitro with IL-2 or in vivo through TLR3 and TLR9 agonists results in increased tumor cell killing and protective anti-tumor effects, respectively. Overall, these results highlight the importance of broad-based immunologic networks in mediating protective anti-tumor responses within our murine challenge system. In particular to SV40 Tag expressing human cancers such as MPM, vaccinating individuals against SV40 Tag while also eliciting innate immunity through TLR sensitization, for example, represents a novel and potentially efficacious immunotherapeutic strategy for patients at high risk for or with established MPM disease.



Simian virus 40, SV40 tag, Malignant pleural mesothelioma