Immunological validation of the EpitOptimizer program for streamlined design of heteroclitic epitopes.
One strategy to generate T-cell responses to tumors is to alter subdominant epitopes through substitution of amino acids that are optimal anchors for specific MHC molecules, termed heteroclitic epitopes. This approach is manually error-prone and time-consuming. In here, we describe a computer-based algorithm (EpitOptimizer) for the streamlined design of heteroclitic epitopes. Analysis of two cancer-related proteins showed that EpitOptimizer-generated peptides have enhanced MHC-I binding compared with their wild-type counterparts; and were able to induce stronger CD8+ T-cell responses against their native epitope. These data demonstrate that this approach can serve as the basis of epitope-engineering against cancer and intracellular pathogens.
Houghton
Colin S B
CS
The Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, United States.
Engelhorn
Manuel E
ME
Liu
Cailan
C
Song
Da
D
Gregor
Polly
P
Livingston
Phillip O
PO
Orlandi
Francesca
F
Wolchok
Jedd D
JD
McCracken
James
J
Houghton
Alan N
AN
Guevara-Patiño
José A
JA
D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D003429:Cross Reactions; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009369:Neoplasms; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015202:Protein Engineering
D019496:Cancer Vaccines; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D010455:Peptides