Role of SEREX-defined immunogenic wild-type cellular molecules in the development of tumor-specific immunity.
Recognition of altered self-antigens in tumor cells by lymphocytes forms the basis for antitumor immune responses. The effector cells in most experimental tumor systems are CD8(+) T cells that recognize MHC class I binding peptides derived from molecules with altered expression in tumor cells. Although the need for CD4(+) helper T cells in regulating CD8(+) T cells has been documented, their target epitopes and functional impact in antitumor responses remain unclear. We examined whether broadly expressed wild-type molecules in murine tumor cells eliciting humoral immunity contributed to the generation of CD8(+) T cells and protective antitumor immune responses to unrelated tumor-specific antigens [mutated ERK2 (mERK2) and c-erbB2/HER/neu (HER2)]. The immunogenic wild-type molecules, presumably dependent on recognition by CD4(+) helper T cells, were defined by serological analysis of recombinant cDNA expression libraries (SEREX) using tumor-derived lambda phage libraries screened with IgG antibodies of hosts bearing transplanted 3-methylchoranthrene-induced tumors. Coimmunization of mice with plasmids encoding SEREX-defined murine wild-type molecules and mERK2 or HER2 led to a profound increase in CD8(+) T cells specific for mERK2 or HER2 peptides. This heightened response depended on CD4(+) T cells and copresentation of SEREX-defined molecules and CD8(+) T cell epitopes. In tumor protection assays, immunization with SEREX-defined wild-type molecules and mERK2 resulted in an inhibition of pulmonary metastasis, which was not achieved by immunization with mERK2 alone.
Nishikawa
H
H
Second Department of Internal Medicine, Department of Gynecology, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
Tanida
K
K
Ikeda
H
H
Sakakura
M
M
Miyahara
Y
Y
Aota
T
T
Mukai
K
K
Watanabe
M
M
Kuribayashi
K
K
Old
L J
LJ
Shiku
H
H
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000939:Epitopes / Q000235:genetics; D005260:Female; D015870:Gene Expression; D007114:Immunization; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D001324:Autoantigens; D000939:Epitopes; D019950:Mitogen-Activated Protein Kinase 1; D018719:Erb-b2 Receptor Tyrosine Kinases