title: Potentiation of a tumor cell susceptibility to autologous CTL killing by restoration of wild-type p53 function.
abstract: Inactivation of p53 has been implicated in many types of tumors particularly in non-small cell lung carcinoma, one of the most common cancers in which p53 mutation has been frequently identified. The aim of this study was to investigate the influence of p53 status on the regulation of tumor susceptibility to specific CTL-mediated cell death. For this purpose, we used a cytotoxic T lymphocyte clone, Heu127, able to lyse the human autologous lung carcinoma cell line, IGR-Heu, in a HLA-A2-restricted manner. Direct genomic DNA sequencing revealed that IGR-Heu expresses a mutated p53 at codon 132 of the exon 5 which results in the loss of p53 capacity to induce the expression of the p53-regulated gene product p21(waf/CIP1). Initial experiments demonstrated that IGR-Heu was resistant to Fas, TNF, and TRAIL apoptotic pathways. This correlated with the lack of p55 TNFRI, Fas, DR4, and DR5 expression. The effect of wild-type (wt) p53 restoration on the sensitization of IGR-Heu to autologous CTL clone lysis was investigated following infection of the tumor cell line with a recombinant adenovirus encoding the wt p53 (Adwtp53). We demonstrate that the restoration of wt p53 expression and function resulted in a significant potentiation of target cell susceptibility to CTL-mediated lysis. The wt p53-induced optimization of tumor cell killing by specific CTL involves at least in part Fas-mediated pathway via induction of CD95 expression by tumor cells but does not appear to interfere with granzyme B cytotoxic pathway.
authors.affiliation: Laboratoire Cytokines et Immunologie des Tumeurs Humaines, Institut National de la Santé et de la Recherche Médicale Unité 487, Institut Fédératif de Recherche 54 Institut Gustave Roussy, Villejuif, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thiery
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dorothée
authors.forename: Hedi
authors.initials: H
authors.lastname: Haddada
authors.forename: Hamid
authors.initials: H
authors.lastname: Echchakir
authors.forename: Catherine
authors.initials: C
authors.lastname: Richon
authors.forename: Rodica
authors.initials: R
authors.lastname: Stancou
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vergnon
authors.forename: Jean
authors.initials: J
authors.lastname: Benard
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D020868:Gene Silencing / Q000276:immunology*; D005822:Genetic Vectors; D053804:Granzymes; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation / Q000276:immunology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology
chemical_list: D009363:Neoplasm Proteins; D018124:Receptors, Tumor Necrosis Factor; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases