Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens.
Peptide vaccines enhance the response of T cells toward tumor antigens and represent a strategy to augment antigen-independent immunotherapies of cancer. However, peptide vaccines that include native tumor antigens rarely prevent tumor growth. We have assembled a set of peptide variants for a mouse-colon tumor model to determine how to improve T-cell responses. These peptides have similar affinity for MHC molecules, but differ in the affinity of the peptide-MHC/T-cell receptor interaction with a tumor-specific T-cell clone. We systematically demonstrated that effective antitumor responses are generated after vaccination with variant peptides that stimulate the largest proportion of endogenous T cells specific for the native tumor antigen. Importantly, we found some variant peptides that strongly stimulated a specific T-cell clone in vitro, but elicited fewer tumor-specific T cells in vivo, and were not protective. The T cells expanded by the effective vaccines responded to the wild-type antigen by making cytokines and killing target cells, whereas most of the T cells expanded by the ineffective vaccines only responded to the peptide variants. We conclude that peptide-variant vaccines are most effective when the peptides react with a large responsive part of the tumor-specific T-cell repertoire.
Jordan
Kimberly R
KR
Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, CO 80206, USA.
McMahan
Rachel H
RH
Kemmler
Charles B
CB
Kappler
John W
JW
Slansky
Jill E
JE
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018411:Spodoptera; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell; D022223:Vaccines, Subunit; D007371:Interferon-gamma