title: Identification of a lung cancer antigen evading CTL attack due to loss of human leukocyte antigen (HLA) class I expression.
abstract: The human lung cancer cell line, C831L, lost HLA class I expression due to a mutation of the β2-microglobulin (β2m) gene, and it may have been the result of immunoediting by CTL cytotoxicity. By restoration of HLA class I expression, we could identify the antigen that may be associated with HLA downregulation. Such an antigen might be a promising target of immunotherapy because it potentially may induce a sufficient immune response to eradicate cancer cells. The CTL clone could be established from lymph node lymphocytes in patient C831 by stimulation with wild-type β2m-transduced C831L (C831L-wβ2m). The CTL clone showed reactivity against C831L-wβ2m in a HLA-B*0702-restricted manner, but not Parental-C831L or autologous normal cells. The cDNA expression cloning method was used to identify the antigen coding gene recognized by the CTL clone. The cDNA clone exhibited a homology with a part of the mRNA that codes for leucine rich repeat containing eight family member A (LRRC8A). A transfection analysis of minigenes indicated that the antigen peptide was derived from protein translated from the downstream of the registered open reading frame in LRRC8A mRNA. The antigenic 9-mer peptide (GPRESRPPA) was identified. The present methodology should be useful to find the crucial tumor antigens, which are potentially associated with loss of HLA expression. Furthermore, such an antigen may help in achieving a better understanding of the immunological escape mechanisms and it may also provide a favorable immune response in cancer immunotherapy.
authors.affiliation: Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Baba
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hanagiri
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Takenoyama
authors.forename: Hironobu
authors.initials: H
authors.lastname: Shiota
authors.forename: Koji
authors.initials: K
authors.lastname: Kuroda
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Shigematsu
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ichiki
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uramoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: So
authors.forename: Kosei
authors.initials: K
authors.lastname: Yasumoto
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology; D045744:Cell Line, Tumor; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape
chemical_list: D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I; C485976:LRRC8A protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger