title: Mechanisms of apoptosis in T cells from patients with renal cell carcinoma.
abstract: Tumors may escape immune recognition and destruction through the induction of apoptosis in activated T lymphocytes. Results from several laboratories suggest that FasL (L/CD95L) expression in tumors may be responsible for this process. In this study of patients with renal cell carcinoma (RCC), we provide evidence for two mechanisms of T-cell apoptosis. One mechanism involves the induction of apoptosis via FasL expression in tumor cells. This is supported by several observations, including the fact that tumor cells in situ as well as cultured cell lines expressed FasL mRNA and protein by a variety of techniques. The FasL in RCC is functional because in coculture experiments, FasL+ tumors induced apoptosis in Fas-sensitive Jurkat T cells and in activated peripheral blood T cells but not in resting peripheral blood T cells. Most importantly, antibody to FasL partially blocked apoptosis of the activated T cells. Moreover, Fas was expressed by T cells derived from the peripheral blood (53% median) and tumor (44.3% median) of RCC patients. Finally, in situ staining for DNA breaks demonstrated apoptosis in a subset of T cells infiltrating renal tumors. These studies also identified a second mechanism of apoptosis in RCC patient peripheral T cells. Whereas these cells did not display DNA breaks when freshly isolated or after culture for 24 h in medium, peripheral blood T cells from RCC patients underwent activation-induced cell death after stimulation with either phorbol 12-myristate 13-acetate/ionomycin or anti-CD3/CD28 antibodies. Apoptosis mediated by exposure to FasL in tumor cells or through T-cell activation may contribute to the failure of RCC patients to develop an effective T-cell-mediated antitumor response.
authors.affiliation: Department of Immunology, The Cleveland Clinic Foundation, Lerner Research Institute, Ohio 44195, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Uzzo
authors.forename: P
authors.initials: P
authors.lastname: Rayman
authors.forename: V
authors.initials: V
authors.lastname: Kolenko
authors.forename: P E
authors.initials: PE
authors.lastname: Clark
authors.forename: T
authors.initials: T
authors.lastname: Bloom
authors.forename: A M
authors.initials: AM
authors.lastname: Ward
authors.forename: L
authors.initials: L
authors.lastname: Molto
authors.forename: C
authors.initials: C
authors.lastname: Tannenbaum
authors.forename: L J
authors.initials: LJ
authors.lastname: Worford
authors.forename: R
authors.initials: R
authors.lastname: Bukowski
authors.forename: R
authors.initials: R
authors.lastname: Tubbs
authors.forename: E D
authors.initials: ED
authors.lastname: Hsi
authors.forename: N H
authors.initials: NH
authors.lastname: Bander
authors.forename: A C
authors.initials: AC
authors.lastname: Novick
authors.forename: J H
authors.initials: JH
authors.lastname: Finke
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001773:Blood Cells / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000276:immunology*; D053938:DNA Fragmentation; D053222:Fas Ligand Protein; D006801:Humans; D020287:In Situ Nick-End Labeling; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells / Q000276:immunology; D007680:Kidney Neoplasms / Q000097:blood / Q000276:immunology*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016853:Muromonab-CD3 / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016853:Muromonab-CD3; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019014:fas Receptor; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate