title: Heteroclitic immunization induces tumor immunity.
abstract: In tumor transplantation models in mice, cytotoxic T lymphocytes (CTLs) are typically the primary effector cells. CTLs recognize major histocompatibility complex (MHC) class I-associated peptides expressed by tumors, leading to tumor rejection. Peptides presented by cancer cells can originate from viral proteins, normal self-proteins regulated during differentiation, or altered proteins derived from genetic alterations. However, many tumor peptides recognized by CTLs are poor immunogens, unable to induce activation and differentiation of effector CTLs. We used MHC binding motifs and the knowledge of class I:peptide:TCR structure to design heteroclitic CTL vaccines that exploit the expression of poorly immunogenic tumor peptides. The in vivo potency of this approach was demonstrated using viral and self-(differentiation) antigens as models. First, a synthetic variant of a viral antigen was expressed as a tumor antigen, and heteroclitic immunization with peptides and DNA was used to protect against tumor challenge and elicit regression of 3-d tumors. Second, a peptide from a relevant self-antigen of the tyrosinase family expressed by melanoma cells was used to design a heteroclitic peptide vaccine that successfully induced tumor protection. These results establish the in vivo applicability of heteroclitic immunization against tumors, including immunity to poorly immunogenic self-proteins.
authors.affiliation: T Cell Development Laboratory, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dyall
authors.forename: W B
authors.initials: WB
authors.lastname: Bowne
authors.forename: L W
authors.initials: LW
authors.lastname: Weber
authors.forename: J
authors.initials: J
authors.lastname: LeMaoult
authors.forename: P
authors.initials: P
authors.lastname: Szabo
authors.forename: Y
authors.initials: Y
authors.lastname: Moroi
authors.forename: G
authors.initials: G
authors.lastname: Piskun
authors.forename: J J
authors.initials: JJ
authors.lastname: Lewis
authors.forename: A N
authors.initials: AN
authors.lastname: Houghton
authors.forename: J
authors.initials: J
authors.lastname: Nikolić-Zugić
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics; D000956:Antigens, Viral / Q000235:genetics; D001324:Autoantigens; D001483:Base Sequence; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D003429:Cross Reactions; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005818:Genetic Engineering; D015395:Histocompatibility Antigens Class I; D007114:Immunization; D008223:Lymphoma / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control*; D016133:Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D001324:Autoantigens; D019496:Cancer Vaccines; D017931:DNA Primers; D015395:Histocompatibility Antigens Class I; D019444:Vaccines, DNA