Mechanisms of apoptosis in T cells from patients with renal cell carcinoma.

Uzzo RG, Rayman P, Kolenko V, Clark PE, Bloom T, Ward AM, Molto L, Tannenbaum C, Worford LJ, Bukowski R, Tubbs R, Hsi ED, Bander NH, Novick AC, Finke JH
Clin Cancer Res. 1999 5 (5): 1219-29

PMID: 10353760

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.

MeSH Terms (22)

Apoptosis Blood Cells Carcinoma, Renal Cell DNA Fragmentation Fas Ligand Protein fas Receptor Humans In Situ Nick-End Labeling Ionomycin Jurkat Cells Kidney Neoplasms Lymphocyte Activation Lymphocytes, Tumor-Infiltrating Membrane Glycoproteins Muromonab-CD3 Neoplasm Proteins Polymerase Chain Reaction RNA, Messenger RNA, Neoplasm T-Lymphocytes, Cytotoxic Tetradecanoylphorbol Acetate Tumor Cells, Cultured

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