title: Restoration of the expression of transporters associated with antigen processing in lung carcinoma increases tumor-specific immune responses and survival.
abstract: A wide variety of human carcinomas have low expression of tumor-associated antigen presentation in the context of MHC class I antigens due to defects in the antigen presentation pathway. This immune evasion mechanism renders many tumors unrecognizable by host immune surveillance mechanisms. The present study examines the expression of HLA, tapasin, transporter associated with antigen processing 1 (TAP1), and beta2 microglobulin in human small cell lung carcinoma and non-small cell lung carcinoma. Immunohistochemical staining showed severe impairment of the antigen presentation pathway in all patients. In order to recover tumor immunogenicity, a nonreplicating adenovirus expressing human TAP1 (AdhTAP1) was used to restore the expression of TAP1 in the antigen presentation pathway-deficient mouse lung carcinoma cell line, CMT.64. Infection of CMT.64 cells with AdhTAP1 increased MHC class I antigen surface expression, antigen presentation, and susceptibility to antigen-specific CTLs. Fluorescence-activated cell sorting and ELISPOT analysis showed that AdhTAP1 treatment significantly increased dendritic cell cross-presentation and cross-priming of tumor antigens. Furthermore, ex vivo and in vivo AdhTAP1 treatment significantly retarded tumor growth and increased survival of mice bearing CMT.64 tumors. Fluorescence-activated cell sorting analysis and immunohistochemical staining showed a significant increase in CD8+ and CD4+ T cells and CD11c+ dendritic cells infiltrating the tumors. The results show that TAP should be considered as a part of the immunotherapies for various cancers because it is likely to provide a general method for increasing immune responses against tumors regardless of the antigenic composition of the tumor or the MHC haplotypes of the host.
authors.affiliation: Michael Smith Laboratories and Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Yuanmei
authors.initials: Y
authors.lastname: Lou
authors.forename: Timothy Z
authors.initials: TZ
authors.lastname: Vitalis
authors.forename: Genc
authors.initials: G
authors.lastname: Basha
authors.forename: Bing
authors.initials: B
authors.lastname: Cai
authors.forename: Susan S
authors.initials: SS
authors.lastname: Chen
authors.forename: Kyung Bok
authors.initials: KB
authors.lastname: Choi
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jeffries
authors.forename: W Mark
authors.initials: WM
authors.lastname: Elliott
authors.forename: Derek
authors.initials: D
authors.lastname: Atkins
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
authors.forename: Wilfred A
authors.initials: WA
authors.lastname: Jefferies
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D000256:Adenoviridae / Q000235:genetics; D000368:Aged; D017951:Antigen Presentation / Q000276:immunology*; D017920:Antiporters / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006680:HLA Antigens / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D017920:Antiporters; D006680:HLA Antigens; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; C073119:TAP1 protein, human; D001613:beta 2-Microglobulin; C107762:tapasin; D007371:Interferon-gamma