| The induction of antitumor immunity is a multi-step process, which includes the capture and processing of tumor antigen by antigen presenting cells (APC), selection and activation of antigen-specific T cells, then recognition and attacking of effector lymphocytes to the tumor cells. However, most of tumor antigen are nonmutated self-antigens, so tumor eradication must be depended on counteracting the self-tolerance. Therefore, the need of effective cancer vaccine is the proper up-take and presentation of tumor antigen by APC so that the specific antitumor response can be intiated.The design of cancer vaccine with potent immunogenicity is an attractive strategy to cancer therapy. Dendritic cells (DC) are the most potent professional APC for the initiation of antigen-specific immune responses, hi addition to their ability to efficiently acquire and process antigens, DC express high levels of MHC class I and class II molecules as well as costimulatory molecules, which are essential to antigen presentation and T cell activation. Thus, they play a crucial role hi the initiation of antitumor immune response. Based on these features and development of the methods for expansion of DC on a large scale from hematopoietic precursors, DC have been attracted great attention as the vehiclesfor the delivery of cancer vaccines. Up to now, most investigations about DC-based vaccines have focused on exploring feasible and effective approaches to loading tumor antigen onto DC for vaccination. In fact, various approaches have been evaluated, including pulsing DC with tumor antigen in the form of protein or peptide, transducing cDNA encoding tumor antigen or tumor RNA into DC, and fusing tumor cells with DC. Among them, genetic modification of DC to express tumor-associated antigen (TAA) has been documented to be efficacious to induce antitumor immunity in many animal models and partial clinical trials. Transfection of DC with an entire TAA gene has several advantages. First, DC may process and present TAA physiologically to T cells and the CTL generation may be more likely to recognize the naturally processed antigenic epitopes. Secondly, TAA gene-modified DC can be armed with the full antigenic determinants spectrum of tumor cells. They may also present MHC II -restricted epitopes to CD4+ T cells. Lastly, DC can express tumor antigens continuously and MHC-peptide complexes for a long periods. Nevertheless, the anti-tumor immunity induced by TAA gene-modified DC vaccine is still limited in clinical trials, suggesting that DC-based vaccine is required to modify to improve the efficacy before widely used. So, the primary aim of our present study is to enhance the therapeutic efficacy of DC-based vaccine by genetic modification of DC.Part I Lymphotactin cotransfection enhances the therapeutic efficacy of dendritic cells genetically modified with melanoma antigen gplOOIn general, DC capture antigen in the periphery and then migrate to T cell areas in lymphoid organs to prime the immune response. The precise molecular mechanisms about DC migration and interactions between DC and T cells are notwell defined now. However, it is becoming increasingly more evident that chemokines play an important role in the migration and recruitment of immune cells including DC, T cells in vivo. Lymphotactin (Lptn) is a C chemokine that specifically regulates the migration of T cells and NK cells. We hypothesized that more potent chemotaxis of antigen-expressing DC on T cells by genetically cotransfected DC with Lptn and TAA might be capable of facilitating the in vivo stimulation of T cells by DC, and consequently favoring DC Ag presentation and T cell activation. Vaccination with DC cotransfected with Lptn and TAA may elicit more significant antitumor effects than the use of TAA gene-modified DC alone. So, in this study, we investigated whether vaccination with DC cotransfected with Lptn and melanoma antigen gplOO could induce protective and therapeutic antitumor response more effectively in a B16 melanoma tumor model.After infectio...
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