Cytotoxic T lymphocytes induce caspase-dependent and -independent cell death in neuroblastomas in a MHC-nonrestricted fashion

Anna De Geer, Rolf Kiessling, Victor Levitsky, Jelena Levitskaya

Research output: Contribution to journalArticle

Abstract

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-α-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.

Original languageEnglish (US)
Pages (from-to)7540-7550
Number of pages11
JournalJournal of Immunology
Volume177
Issue number11
StatePublished - Dec 1 2006
Externally publishedYes

Fingerprint

Cytotoxic T-Lymphocytes
Caspases
Neuroblastoma
Cell Death
Neoplasms
Bystander Effect
Caspase Inhibitors
Therapeutic Uses
Necrosis
Clone Cells
Apoptosis
Cytokines
T-Lymphocytes
Cell Line

ASJC Scopus subject areas

  • Immunology

Cite this

Cytotoxic T lymphocytes induce caspase-dependent and -independent cell death in neuroblastomas in a MHC-nonrestricted fashion. / De Geer, Anna; Kiessling, Rolf; Levitsky, Victor; Levitskaya, Jelena.

In: Journal of Immunology, Vol. 177, No. 11, 01.12.2006, p. 7540-7550.

Research output: Contribution to journalArticle

De Geer, A, Kiessling, R, Levitsky, V & Levitskaya, J 2006, 'Cytotoxic T lymphocytes induce caspase-dependent and -independent cell death in neuroblastomas in a MHC-nonrestricted fashion', Journal of Immunology, vol. 177, no. 11, pp. 7540-7550.
De Geer, Anna ; Kiessling, Rolf ; Levitsky, Victor ; Levitskaya, Jelena. / Cytotoxic T lymphocytes induce caspase-dependent and -independent cell death in neuroblastomas in a MHC-nonrestricted fashion. In: Journal of Immunology. 2006 ; Vol. 177, No. 11. pp. 7540-7550.
@article{cd438e68969a4044a720f35fdd0f3dc2,
title = "Cytotoxic T lymphocytes induce caspase-dependent and -independent cell death in neuroblastomas in a MHC-nonrestricted fashion",
abstract = "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-α-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.",
author = "{De Geer}, Anna and Rolf Kiessling and Victor Levitsky and Jelena Levitskaya",
year = "2006",
month = "12",
day = "1",
language = "English (US)",
volume = "177",
pages = "7540--7550",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "11",

}

TY - JOUR

T1 - Cytotoxic T lymphocytes induce caspase-dependent and -independent cell death in neuroblastomas in a MHC-nonrestricted fashion

AU - De Geer, Anna

AU - Kiessling, Rolf

AU - Levitsky, Victor

AU - Levitskaya, Jelena

PY - 2006/12/1

Y1 - 2006/12/1

N2 - 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-α-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.

AB - 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-α-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.

UR - http://www.scopus.com/inward/record.url?scp=33751568511&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33751568511&partnerID=8YFLogxK

M3 - Article

VL - 177

SP - 7540

EP - 7550

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 11

ER -