Antitumor cytotoxic T-lymphocyte response in human lung carcinoma: identification of a tumor-associated antigen.
We have isolated several cytotoxic T lymphocyte (CTL) clones from lymphocytes infiltrating a lung carcinoma of a patient with long survival. These clones showed a CD3+, CD8+, CD4-, CD28- phenotype and expressed a T-cell receptor (TCR) encoded either by Vbeta8-Jbeta1.5 or Vbeta22-Jbeta1.4 rearrangements. Functional studies indicated that these clones mediated a high human leukocyte antigen (HLA)-A2.1-restricted cytotoxic activity against the autologous tumor cell line. Interestingly, TCRbeta chain gene usage indicated that CTL clones identified in vitro were selectively expanded in vivo at the tumor site as compared to autologous peripheral blood lymphocytes (PBL). These findings provide evidence that an immune response may take place in non-small cell lung carcinoma and that effector T cells may contribute to tumor regression. Further study indicated that the CTL clones recognized the same decamer peptide encoded by a mutated alpha-actinin-4 gene. Using tetramers of soluble HLA-A2 molecules loaded with the mutated antigenic peptide, we have derived several anti-alpha-actinin-4 T-cell clones from patient PBL. These CTL, recognizing a truly tumor-specific antigen, may play a role in the clinical evolution of this lung cancer patient. Adoptive transfer of CTL clones in a SCID/NOD mice model transplanted with autologous tumor supported their antitumor effect in vivo.
Mami-Chouaib
Fathia
F
Laboratoire Cytokines et Immunologie des tumeurs Humaines, U487 INSERM, Institut Fédératif de Recherche-54, Institut Gustave Roussy, Villejuif, France. cfathia@igr.fr
Echchakir
Hamid
H
Dorothée
Guillaume
G
Vergnon
Isabelle
I
Chouaib
Salem
S
D000185:Actinin / Q000737:chemistry / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000473:pathology; D002999:Clone Cells / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
C111453:ACTN4 protein, human; C491752:Actn4 protein, mouse; D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D000185:Actinin