Retrovirally transduced human dendritic cells can generate T cells recognizing multiple MHC class I and class II epitopes from the melanoma antigen glycoprotein 100.
Involvement of tumor-Ag specific CD4(+) and CD8(+) T cells could be critical in the generation of an effective immunotherapy for cancer. In an attempt to optimize the T cell response against defined tumor Ags, we previously developed a method allowing transgene expression in human dendritic cells (DCs) using retroviral vectors. One advantage of using gene-modified DCs is the potential ability to generate CD8(+) T cells against multiple class I-restricted epitopes within the Ag, thereby eliciting a broad antitumor immune response. To test this, we generated tumor-reactive CD8(+) T cells with DCs transduced with the melanoma Ag gp100, for which a number of HLA-A2-restricted epitopes have been described. Using gp100-transduced DCs, we were indeed able to raise T cells recognizing three distinct HLA-A2 epitopes within the Ag, gp100(154-162), gp100(209-217), and gp100(280-288). We next tested the ability of transduced DCs to raise class II-restricted CD4(+) T cells. Interestingly, stimulation with gp100-transduced DCs resulted in the generation of CD4(+) T cells specific for a novel HLA-DRbeta1*0701-restricted epitope of gp100. The minimal determinant of this epitope was defined as gp100(174-190) (TGRAMLGTHTMEVTVYH). These observations suggest that retrovirally transduced DCs have the capacity to present multiple MHC class I- and class II-restricted peptides derived from a tumor Ag, thereby eliciting a robust immune response against that Ag.
Lapointe
R
R
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Royal
R E
RE
Reeves
M E
ME
Altomare
I
I
Robbins
P F
PF
Hwu
P
P
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D018952:Antigens, CD34 / Q000302:isolation & purification; D003713:Dendritic Cells / Q000276:immunology*; D000939:Epitopes; D005822:Genetic Vectors; D015789:HLA-A2 Antigen / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D008545:Melanoma / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D010455:Peptides; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014170:Transformation, Genetic; D058951:gp100 Melanoma Antigen
D018952:Antigens, CD34; D000939:Epitopes; D015789:HLA-A2 Antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D010455:Peptides; D058951:gp100 Melanoma Antigen; C548641:gp100(280-288) melanoma antigen peptide