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

Ann N Y Acad Sci. 2009 Sep;1174:6-17. doi: 10.1111/j.1749-6632.2009.04933.x.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibody Formation / immunology
  • Antigens, CD / drug effects
  • Antigens, CD / immunology*
  • Antigens, Neoplasm / immunology*
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Colony-Stimulating Factors / immunology
  • Colony-Stimulating Factors / pharmacology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / immunology
  • GPI-Linked Proteins
  • Humans
  • Immunization / methods
  • Lectins, C-Type / drug effects
  • Lectins, C-Type / immunology*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Minor Histocompatibility Antigens
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / immunology*
  • Receptors, Interferon / deficiency

Substances

  • Antigens, CD
  • Antigens, Neoplasm
  • Colony-Stimulating Factors
  • DEC-205 receptor
  • Epitopes
  • GPI-Linked Proteins
  • Lectins, C-Type
  • Membrane Glycoproteins
  • Minor Histocompatibility Antigens
  • Receptors, Cell Surface
  • Receptors, Interferon
  • interferon gamma receptor
  • mesothelin