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Decreased sensitivity of drug-resistant cells towards T cell cytotoxicity

C F Classen1, S Fulda, C Friesen

  • 1University Children's Hospital Ulm, Germany.

Leukemia
|March 23, 1999
PubMed

Insights

Tumor cells resistant to apoptosis show cross-resistance to cytotoxic T cell killing. This resistance, linked to deficient caspase activation, impacts immunotherapy strategies for tumors previously treated with chemotherapy.

Area of Science:

  • Immunology
  • Cell Biology
  • Cancer Research

Background:

  • Cytotoxic T cell-mediated killing of target cells relies on apoptosis induction via CD95 or perforin/granzyme pathways.
  • Tumor cells can develop resistance to apoptosis, potentially affecting their susceptibility to immune attack.

Purpose of the Study:

  • To investigate the mechanisms of apoptosis resistance in tumor cells.
  • To determine the cross-resistance patterns of tumor cells against different apoptotic stimuli and cytotoxic T cell-mediated killing.
  • To explore the implications of apoptosis resistance for cancer immunotherapy.

Main Methods:

  • Comparison of SH-EP neuroblastoma and CEM T leukemia cell lines for sensitivity to CD95- and perforin/granzyme-mediated killing.
  • Assessment of apoptosis induction and caspase activation (PARP cleavage) in resistant and sensitive cells.
  • Evaluation of the effect of caspase inhibition (zVAD-fmk) and preincubation with doxorubicin on cytotoxic T cell kill.

Main Results:

  • SH-EP cells were primarily killed via CD95, while CEM cells involved both CD95 and perforin/granzyme pathways.
  • Cells resistant to CD95- or drug-induced apoptosis exhibited cross-resistance to cytotoxic T cell killing.
  • Resistant cells displayed reduced apoptosis and impaired caspase activation, evidenced by decreased PARP cleavage.
  • Caspase inhibition significantly reduced T cell-mediated killing in sensitive cells.
  • Doxorubicin could sensitize parental CEM cells but not revert resistance in pre-existing resistant CEM cells.

Conclusions:

  • Tumor cells exhibit cross-resistance to apoptosis induced by various cytotoxic agents and T cell-mediated killing.
  • Deficient caspase activation is a key feature of apoptosis-resistant tumor cells.
  • Apoptosis resistance in tumors, potentially induced by prior chemotherapy, may pose challenges for effective immunotherapy.

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