A retrogen strategy for presentation of an intracellular tumor antigen as an exogenous antigen by dendritic cells induces potent antitumor T helper and CTL responses

Induction of an effective antitumor response requires CD4+ helper T (Th) ce lls to recognize antigens on the same dendritic cells (DCs) that cross-pres ent CTL antigens, Such cross-presentation is difficult to achieve by curren t tumor vaccine strategies. Here, we develop a novel "Retrogen" strategy fo r DCs to efficiently cross-present an intracellular tumor antigen, MAGE-3, to both MHC class I and MHC class II in a cognate manner. Specifically, the MAGE-3 gene was linked to a leader sequence at its NH2 terminus for secret ion and to a cell-binding domain at its COOH terminus for receptor-mediated internalization. DCs transduced with the modified MAGE-3 gene produced and secreted MAGE-3 proteins, which were efficiently taken up by DCs via recep tor-mediated internalization and presented as exogenous antigens to class I and class II molecules, Immunization of mice with the transduced DCs expre ssing the MAGE-3 fusion protein, termed "Retrogen" for its retrograde trans part/internalization after secretion, efficiently induced all arms of the a daptive antitumor immune responses. Thus, this retrogen strategy of using a unifying mechanism for DCs to cross-present an intracellular tumor antigen in a cognate manner could be generally used to improve the efficacy of tum or vaccines and immunotherapies.