Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide-TCR complex.
T cell responsiveness to an epitope is affected both by its affinity for the presenting MHC molecule and the affinity of the MHC-peptide complex for TCR. One limitation of cancer immunotherapy is that natural tumor antigens elicit relatively weak T cell responses, in part because high-affinity T cells are rendered tolerant to these antigens. We report here that amino acid substitutions in a natural MHC class I-restricted tumor antigen that increase the stability of the MHC-peptide-TCR complex are significantly more potent as tumor vaccines. The improved immunity results from enhanced in vivo expansion of T cells specific for the natural tumor epitope. These results indicate peptides that stabilize the MHC-peptide-TCR complex may provide superior antitumor immunity through enhanced stimulation of specific T cells.
Slansky
J E
JE
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Rattis
F M
FM
Boyd
L F
LF
Fahmy
T
T
Jaffee
E M
EM
Schneck
J P
JP
Margulies
D H
DH
Pardoll
D M
DM
D000409:Alanine / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D002999:Clone Cells; D015179:Colorectal Neoplasms / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006183:H-2 Antigens / Q000378:metabolism*; D064532:Histocompatibility Antigen H-2D; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D016176:T-Lymphocyte Subsets / Q000276:immunology
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D008024:Ligands; D009842:Oligopeptides; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D000409:Alanine