title: A thyroid tumor-specific antigen formed by the fusion of two self proteins.
abstract: Thyroid epithelial cells frequently express one or more members of the rearranged during transfection/papillary thyroid carcinoma (RET/PTC) fusion oncogene family during early stages of cancer, and fusion gene transcripts have been found in inflammatory conditions of the thyroid such as the autoimmune disease, Hashimoto's thyroiditis. Because these oncogenes encode chimeric proteins, novel RET/PTC epitopes may be targets of antitumor immune responses. We have been interested in the RET/PTC3 (RP3) fusion protein because this family member is more frequently expressed in radiation-induced and childhood papillary carcinomas than other members of the fusion oncogene family. We hypothesized that the activated kinase of c-RET, in the form of RP3, when expressed in patients with thyroid disease, presents an unusual altered self target for T cell recognition. Interestingly, we find that immunization with mouse RP3 protein can induce a strongly immunogenic response to RP3, although this response is not directed against the peptide comprising the unique fusion region. Rather, the responses are specific for the carboxyl-terminal portion of RP3 that is derived from the self protein c-RET. Furthermore, transplantation of RP3-expressing thyroid tumors into naive mice resulted in leukocytic infiltration, tumor rejection, and induction of RP3-specific T cells. Thus, the somatic fusion of two unrelated self proteins results in the development of a uniquely immunogenic response directed against self epitopes within RP3. These studies may better define the mechanisms controlling the initiation of thyroid-specific immune responses and provide insight into the design of novel molecules for invoking tumor-specific immunity.
authors.affiliation: Department of Microbiology/Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
authors.forename: Laurence C
authors.initials: LC
authors.lastname: Eisenlohr
authors.forename: Jay L
authors.initials: JL
authors.lastname: Rothstein
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D001324:Autoantigens / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D016175:B-Lymphocyte Subsets / Q000276:immunology; D029721:Drosophila Proteins; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005136:Eye Proteins; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics; D007114:Immunization; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary / Q000235:genetics; D011506:Proteins / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013961:Thyroid Gland / Q000378:metabolism / Q000637:transplantation; D013964:Thyroid Neoplasms / Q000235:genetics / Q000276:immunology*; D013967:Thyroiditis, Autoimmune / Q000235:genetics / Q000276:immunology; D014615:Vaccinia / Q000235:genetics / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D029721:Drosophila Proteins; D018984:Epitopes, T-Lymphocyte; D005136:Eye Proteins; D000949:Histocompatibility Antigens Class II; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D011518:Proto-Oncogene Proteins; C099929:RPGR protein, human; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse