Autologous human monocyte-derived dendritic cells genetically modified to express melanoma antigens elicit primary cytotoxic T cell responses in vitro: Enhancement by cotransfection of genes encoding the Th1-biasing cytokines IL-12 and IFN-α

Thomas Tüting, Cara C. Wilson, Dina M. Martin, Yvette L. Kasamon, Jennifer Rowles, Debora I. Ma, Craig L. Slingluff, Stephan N. Wagner, Pierre Van Der Bruggen, Joseph Baar, Michael T. Lotze, Walter J. Storkus

Research output: Contribution to journalArticle

Abstract

DNA-based immunization strategies designed to elicit cellular antitumor immunity offer an attractive alternative to protein- or peptide-based approaches. In the present study we have evaluated the feasibility of DNA vaccination for the induction of CTL reactivity to five different melanoma Ags in vitro. Cultured, monocyte-derived dendritic cells (DC) were transiently transfected with plasmid DNA encoding human MART-1/Melan-A, pMel- 17/gp100, tyrosinase, MAGE-1, or MAGE-3 by particle bombardment and used to stimulate autologous PBMC responder T cells. CTL reactivity to these previously identified melanoma Ags was reproducibly generated after two or three stimulations with genetically modified DC. Co-ordinate transfection of two melanoma Ag cDNAs into DC promoted CTL responders capable of recognizing epitopes from both gene products. Coinsertion of genes encoding the Th1- biasing cytokines IL-12 or IFN-α consistently enhanced the magnitude of the resulting Ag-specific CTL reactivity. Importantly, DC transfected with a single melanoma Ag cDNA were capable of stimulating Ag-specific CTL reactivity restricted by multiple host MHC alleles, some of which had not been previously identified. These results support the inherent strengths of gene-based vaccine approaches that do not require prior knowledge of responder MHC haplotypes or of relevant MHC-restricted peptide epitopes. Given previous observations of in situ tumor HLA allele-loss variants, DC gene vaccine strategies may elicit a greater diversity of host therapeutic immunity, thereby enhancing the clinical utility and success of such approaches.

Original languageEnglish (US)
Pages (from-to)1139-1147
Number of pages9
JournalJournal of Immunology
Volume160
Issue number3
StatePublished - Feb 1 1998
Externally publishedYes

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Melanoma-Specific Antigens
Interleukin-12
Dendritic Cells
Monocytes
Cytokines
Melanoma
T-Lymphocytes
Genes
Epitopes
DNA
Vaccines
Complementary DNA
Alleles
MART-1 Antigen
Peptides
Monophenol Monooxygenase
Cellular Immunity
Haplotypes
Transfection
Immunity

ASJC Scopus subject areas

  • Immunology

Cite this

Autologous human monocyte-derived dendritic cells genetically modified to express melanoma antigens elicit primary cytotoxic T cell responses in vitro : Enhancement by cotransfection of genes encoding the Th1-biasing cytokines IL-12 and IFN-α. / Tüting, Thomas; Wilson, Cara C.; Martin, Dina M.; Kasamon, Yvette L.; Rowles, Jennifer; Ma, Debora I.; Slingluff, Craig L.; Wagner, Stephan N.; Van Der Bruggen, Pierre; Baar, Joseph; Lotze, Michael T.; Storkus, Walter J.

In: Journal of Immunology, Vol. 160, No. 3, 01.02.1998, p. 1139-1147.

Research output: Contribution to journalArticle

Tüting, T, Wilson, CC, Martin, DM, Kasamon, YL, Rowles, J, Ma, DI, Slingluff, CL, Wagner, SN, Van Der Bruggen, P, Baar, J, Lotze, MT & Storkus, WJ 1998, 'Autologous human monocyte-derived dendritic cells genetically modified to express melanoma antigens elicit primary cytotoxic T cell responses in vitro: Enhancement by cotransfection of genes encoding the Th1-biasing cytokines IL-12 and IFN-α', Journal of Immunology, vol. 160, no. 3, pp. 1139-1147.
Tüting, Thomas ; Wilson, Cara C. ; Martin, Dina M. ; Kasamon, Yvette L. ; Rowles, Jennifer ; Ma, Debora I. ; Slingluff, Craig L. ; Wagner, Stephan N. ; Van Der Bruggen, Pierre ; Baar, Joseph ; Lotze, Michael T. ; Storkus, Walter J. / Autologous human monocyte-derived dendritic cells genetically modified to express melanoma antigens elicit primary cytotoxic T cell responses in vitro : Enhancement by cotransfection of genes encoding the Th1-biasing cytokines IL-12 and IFN-α. In: Journal of Immunology. 1998 ; Vol. 160, No. 3. pp. 1139-1147.
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abstract = "DNA-based immunization strategies designed to elicit cellular antitumor immunity offer an attractive alternative to protein- or peptide-based approaches. In the present study we have evaluated the feasibility of DNA vaccination for the induction of CTL reactivity to five different melanoma Ags in vitro. Cultured, monocyte-derived dendritic cells (DC) were transiently transfected with plasmid DNA encoding human MART-1/Melan-A, pMel- 17/gp100, tyrosinase, MAGE-1, or MAGE-3 by particle bombardment and used to stimulate autologous PBMC responder T cells. CTL reactivity to these previously identified melanoma Ags was reproducibly generated after two or three stimulations with genetically modified DC. Co-ordinate transfection of two melanoma Ag cDNAs into DC promoted CTL responders capable of recognizing epitopes from both gene products. Coinsertion of genes encoding the Th1- biasing cytokines IL-12 or IFN-α consistently enhanced the magnitude of the resulting Ag-specific CTL reactivity. Importantly, DC transfected with a single melanoma Ag cDNA were capable of stimulating Ag-specific CTL reactivity restricted by multiple host MHC alleles, some of which had not been previously identified. These results support the inherent strengths of gene-based vaccine approaches that do not require prior knowledge of responder MHC haplotypes or of relevant MHC-restricted peptide epitopes. Given previous observations of in situ tumor HLA allele-loss variants, DC gene vaccine strategies may elicit a greater diversity of host therapeutic immunity, thereby enhancing the clinical utility and success of such approaches.",
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AU - Wilson, Cara C.

AU - Martin, Dina M.

AU - Kasamon, Yvette L.

AU - Rowles, Jennifer

AU - Ma, Debora I.

AU - Slingluff, Craig L.

AU - Wagner, Stephan N.

AU - Van Der Bruggen, Pierre

AU - Baar, Joseph

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