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) cells to recognize antigens on the same dendritic cells (DCs) that cross-present CTL antigens. Such cross-presentation is difficult to achieve by current tumor vaccine strategies. Here, we develop a novel "Retrogen" strategy for 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 secretion 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 receptor-mediated internalization and presented as exogenous antigens to class I and class II molecules. Immunization of mice with the transduced DCs expressing the MAGE-3 fusion protein, termed "Retrogen" for its retrograde transport/internalization after secretion, efficiently induced all arms of the adaptive 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 tumor vaccines and immunotherapies.
You
Z
Z
Center for Cell and Gene Therapy, and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Hester
J
J
Rollins
L
L
Spagnoli
G C
GC
van der Bruggen
P
P
Chen
S Y
SY
D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D003429:Cross Reactions; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D013945:Thymoma / Q000276:immunology / Q000517:prevention & control; D014161:Transduction, Genetic
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D007141:Immunoglobulin Fc Fragments; C072013:MAGEA3 protein, human; C489519:Mageb3 protein, mouse; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins