Cytotoxic T lymphocytes induce caspase-dependent and -independent cell death in neuroblastomas in a MHC-nonrestricted fashion.
The MHC class I- restricted processing and presentation pathway is frequently nonfunctional in tumor cells; therefore, the direct targeting of tumor cells by CTLs may be difficult, if at all possible, to achieve. We used neuroblastoma (NB), which represents a striking example of a tumor with an impaired MHC class I pathway, as a model to study bystander effects of activated T lymphocytes on tumor cells. We found that NB cell lines are susceptible to killing by differentiated CD8(+) CTL clones in a MHC class I-nonrestricted manner that involves two programs of cell death distinguished on the basis of different kinetics, sensitivities to caspase inhibitors, and cytokine-blocking reagents. The "early" death exhibited characteristic features of apoptosis, whereas the "delayed" caspase-independent death exhibited features associated with necrosis and was partially inhibited by TNF-alpha-blocking and prevented by overexpression of Bcl-2 or Bcl-x(L). Our data reveal a previously unappreciated complexity of death pathways induced in tumor cells by immune activation and suggest that redirecting nonspecific effector CTLs to even a small proportion of NB cells or activating CTLs in a tumor's proximity may have therapeutic effects in patients with NB.
De Geer
Anna
A
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, S-17176 Stockholm, Sweden.
Kiessling
Rolf
R
Levitsky
Victor
V
Levitskaya
Jelena
J
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D024201:Bystander Effect / Q000276:immunology*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008285:Major Histocompatibility Complex; D051379:Mice; D009447:Neuroblastoma / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D014162:Transfection
D020169:Caspases