B7.1 on human carcinomas: costimulation of T cells and enhanced tumor-induced T-cell death.
Human squamous cell carcinomas of the head and neck (SCCHN) do not express the costimulatory molecules B7.1 or B7.2 in situ or in culture. Transduction of B7.1(-) SCCHN cells with the retroviral B7. 1 and neo(r) genes resulted in the expression of high levels of the transgene in these tumor cells. When B7.1(+) SCCHN cells were used as stimulators of autologous or allogeneic PBL in mixed lymphocyte-tumor cultures (MLTC), T-cell proliferation and generation of antitumor effector T cells as well as levels of their lytic activity were significantly increased. At the same time, a proportion of activated T cells seen to undergo apoptosis was found to be significantly higher upon coincubation with B7.1(+) SCCHN than with B7.1(-) SCCHN. Both B7.1(+) and B7.1(-) SCCHN cells were found to express FasL on the cell surface and in the cytoplasm, as well as mRNA for FasL and mRNA for TRAIL. However, expression of the B7.1 transgene did not lead to increased expression of FasL protein on tumor cells. Yet, up to 50% of activated CD28(+) allogeneic T cells, which were CD95(+), showed evidence of DNA fragmentation in JAM and TUNEL assays upon incubation with an excess of B7.1(+) SCCHN for 24 h. Tumor-induced T-cell death was equally and only in part blocked by anti-Fas antibodies in both B7.1(+) and B7.1(-) MLTC. While surface expression of B7.1 molecules on SCCHN cells enhanced T-cell costimulation via B7.1-CD28 interactions, it did not rescue activated T cells from tumor-induced apoptosis. The outcome of MLTC under these conditions was dependent on the ratio of tumor to T cells. Thus, in the presence of an excess of B7.1(+) tumor cells, activated T cells showed increased sensitivity to apoptosis which did not appear to be Fas/FasL mediated. These data are important for the development of B7.1 gene therapy and efforts directed at the generation of effector cells in MLTC.
Lang
S
S
Department of Pathology, University of Pittsburgh Cancer Institute, PA 15213, USA.
Atarashi
Y
Y
Nishioka
Y
Y
Stanson
J
J
Meidenbauer
N
N
Whiteside
T L
TL
D017209:Apoptosis; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology*; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D006258:Head and Neck Neoplasms / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic; D014170:Transformation, Genetic; D019076:Transgenes; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
D018122:B7-1 Antigen; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor