title: Deficiency of transporter for antigen presentation (TAP) in tumor cells allows evasion of immune surveillance and increases tumorigenesis.
abstract: Proteins involved in class I MHC (MHC-I) Ag processing, such as the TAP, are deficient in some human tumor cells. This suggests that antitumor responses by CD8 T cells provide selection pressure to favor outgrowth of cells with defective processing of tumor Ags. Nonetheless, this evidence is only correlative, and controlled in vivo experiments have been lacking to demonstrate that TAP deficiency promotes survival of tumor cells. To explore the role of Ag processing defects in tumor progression, matched panels of TAP1-positive and TAP1-negative tumor cell lines were generated from a parental transformed murine fibroblast line. Inoculation of C57BL/6 mice with TAP1-negative cells produced large and persistent tumors. In contrast, TAP1-positive cells did not generate lasting tumors, although small tumors were detected transiently and regressed spontaneously. Both TAP1-positive and TAP1-negative cells produced tumors in athymic mice, confirming that TAP-dependent differences in tumorigenicity were due to T cell-dependent immune responses. Inoculation of C57BL/6 mice with mixtures of TAP1-positive and TAP1-negative cells produced tumors composed exclusively of TAP1-negative cells, indicating in vivo selection for cells with TAP deficiency. Thus, loss of TAP function allows some tumor cells to avoid T cell-dependent elimination, resulting in selection for tumor cells with deficient Ag processing.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Johnsen
authors.forename: D J
authors.initials: DJ
authors.lastname: Templeton
authors.forename: M
authors.initials: M
authors.lastname: Sy
authors.forename: C V
authors.initials: CV
authors.lastname: Harding
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D012333:RNA, Messenger / Q000096:biosynthesis; D012513:Sarcoma, Experimental / Q000209:etiology / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D012333:RNA, Messenger; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse