The human cancer antigen mesothelin is more efficiently presented to the mouse immune system when targeted to the DEC-205/CD205 receptor on dendritic cells.
To develop a tumor vaccine directly targeting tumor antigen to dendritic cells in situ, we engineered human mesothelin (MSLN) into an antibody specific for mouse DEC-205, a receptor for antigen presentation. We then characterized both T cell and humoral responses to human MSLN and compared immunizing efficacy of DEC-205-targeted MSLN to nontargeted protein after a single-dose immunization. Targeting human MSLN to DEC-205 receptor induced stronger CD4(+) T-cell responses compared to high doses of mesothelin protein. Approximately 0.5% CD4(+) T cells were primed to produce IFN-gamma, tumor necrosis factor-alpha, and IL-2 via intracellular cytokine staining, and the T cells also could proliferate rapidly. The immune response exhibited breadth because the primed CD4(+) T cells responded to at least three epitopes in the H-2(b) background. Targeting MSLN protein to DEC-205 receptor also resulted in cross-presentation to CD8(+) T cells. Antibody responses against human MSLN were also detected in serum from primed mice by ELISA assays. In summary, targeting of MSLN to DEC-205 improves the induction of CD4(+) and CD8(+) T-cell immunity accompanied by an antibody response. DEC-205-targeting could be valuable for enhancing immunity to MSLN in cancers where this nonmutated protein is expressed.
Wang
Bei
B
Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, NY 10065, USA.
Kuroiwa
Janelle M Y
JM
He
Li-Zhen
LZ
Charalambous
Anna
A
Keler
Tibor
T
Steinman
Ralph M
RM
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003115:Colony-Stimulating Factors / Q000276:immunology / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D058851:GPI-Linked Proteins; D006801:Humans; D007114:Immunization / Q000379:methods; D037181:Lectins, C-Type / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D000090204:Mesothelin; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000276:immunology*; D017471:Receptors, Interferon / Q000172:deficiency; D000096743:Interferon gamma Receptor
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D003115:Colony-Stimulating Factors; D000939:Epitopes; D058851:GPI-Linked Proteins; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D000090204:Mesothelin; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C093569:DEC-205 receptor; C000715527:MSLN protein, human; C000715528:Msln protein, mouse