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Cytotoxic T Lymphocytes Induce Caspase-Dependent and -Independent Cell Death in Neuroblastomas in a MHC-Nonrestricted Fashion¹

Anna De Geer^*, Rolf Kiessling^*, Victor Levitsky and Jelena Levitskaya^2,*

^* Department of Oncology-Pathology, Cancer Centrum Karolinska and Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

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--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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Swedish Children’s Cancer Foundation, the Swedish Cancer Society, the Cancer Society of Stockholm, the King Gustav V Jubilee Fund, and the Swedish Research Council.

² Address correspondence and reprint requests to Dr. Jelena Levitskaya, Immune and Gene Therapy Unit, Cancer Centrum Karolinska, Karolinska Hospital, KS-ringen, R8:01, S-17176 Stockholm, Sweden. E-mail address: Elena.Levitskaya{at}ki.se

³ Abbreviations used in this paper: NB, neuroblastoma; AS, activated supernatant; CS, control supernatant; HMGB1, high mobility group B1 protein; fmk, fluoromethyl ketone; LCL, lymphoblastoid cell line; PARP, poly(ADP-ribose) polymerase; PI, propidium iodide; TMRE, tetramethylrhodamine ethyl ester perchlorate; Z, benzyloxycarbonyl.

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