Competition among peptides in melanoma vaccines for binding to MHC molecules.
The effectiveness of peptide-based cancer vaccines depends on the ability of peptides to bind to MHC molecules on the surface of antigen-presenting cells, where they reconstitute epitopes for cytotoxic T lymphocytes (CTLs). Multivalent vaccines have advantages over single-peptide vaccines; however, peptides may compete for binding to the same MHC molecules. In particular, it is possible that peptides with high affinity for MHC molecules prevent the binding of lower-affinity peptides. However, only small numbers of peptide/MHC complexes per cell are required for CTL recognition. Thus, the authors hypothesized that competition of peptides for MHC binding would not significantly reduce CTL recognition of individual peptides within a multiple-peptide mixture, and this hypothesis was tested by a series of experiments performed in vitro. In multiple experiments, two peptides with different affinities for HLA-A*0201 molecules were mixed at various concentrations and pulsed onto HLA-A2 cells, which were then evaluated for susceptibility to lysis by HLA-A*0201-restricted CTLs. CTL recognition of the melanoma peptides gp100(154-162) (KTWGQYWQV), gp100(280-288) (YLEPGPVTA), and tyrosinase(369-377D) (YMDGTMSQV) was maintained even when target cells were co-pulsed with equimolar concentrations of peptides with comparable or higher affinity for HLA-A2. In some cases, CTL recognition was maintained even when the higher-affinity peptide was present at concentrations several orders of magnitude higher than the target peptide. In addition, CTLs generated by in vitro stimulation with a peptide mixture developed reactivity to three different peptides, at a level comparable to that obtained by stimulation with each individual peptide separately. These data suggest that CTLs can respond to multiple peptides presented on the same antigen-presenting cells and justify further investigation, in clinical trials, of multiple-peptide cancer vaccines.
Thompson
Lee W
LW
Department of Surgery, Division of Surgical Oncology, University of Virginia Health System, Charlottesville, Virginia, USA.
Garbee
Courtney F
CF
Hibbitts
Sarah
S
Brinckerhoff
Laurence H
LH
Pierce
Richard A
RA
Chianese-Bullock
Kimberly A
KA
Deacon
Donna H
DH
Engelhard
Victor H
VH
Slingluff
Craig L
CL
D001667:Binding, Competitive; D019496:Cancer Vaccines / Q000276:immunology*; D002460:Cell Line; D015234:HLA-A Antigens / Q000378:metabolism*; D015789:HLA-A2 Antigen; D006801:Humans; D008545:Melanoma / Q000276:immunology*; D014442:Monophenol Monooxygenase / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D019496:Cancer Vaccines; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D014442:Monophenol Monooxygenase