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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 2015-2023
Tumor-induced apoptosis of T lymphocytes: elucidation of
intracellular apoptotic events
Brian R. Gastman,
Daniel E. Johnson,
Theresa L. Whiteside, and
Hannah Rabinowich
From the Departments of Pathology, Pharmacology, Medicine, and
Otolaryngology, University of Pittsburgh School of Medicine and
University of Pittsburgh Cancer Institute, Pittsburgh, PA.
Our recent studies suggest that human squamous cell carcinoma of the
head and neck (SCCHN) is capable of activating an intrinsic mechanism
of programmed-cell death in interacting lymphocytes in situ and in
vitro. The current study used Jurkat T-cell line as a model to
investigate intracellular apoptotic events in T cells interacting with
SCCHN. Apoptosis induced in T lymphocytes by tumor cells was in part
Fas-mediated, since it was partially, but significantly, inhibited in
the presence of anti-Fas ligand Ab or in Fas-resistant Jurkat cells.
The synthetic caspase inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) and
N-benzyloxycarbonyl-Asp-glu-Val-Asp-fluoromethyl ketone (Z-DEVD-FMK), effectively blocked apoptosis of Jurkat cells co-incubated with SCCHN
cell lines, suggesting the involvement of caspases in tumor-induced apoptosis of lymphocytes. Overexpression of CrmA, an inhibitor of
caspase-1 and caspase-8, partially inhibited tumor-induced T-cell
death. Caspase-8 and caspase-3 were identified as effector molecules in
the execution of tumor-induced T-cell death, since the proform enzymes
were processed into active subunits during co-incubation of T cells
with tumor cells. Furthermore, co-incubation with tumor cells resulted
in cleavage of poly(ADP-ribose) polymerase (PARP), a common caspase-3
substrate, and in cleavage of TcR- chain, shown by us to be a T-cell
specific caspase-3 substrate. Overexpression of Bcl-2 did not provide
protection of T cells from SCCHN-induced DNA degradation. Instead, the
Bcl-2 protein was cleaved in the target T cells during their
co-incubation with tumor cells. These findings demonstrate that tumor
cells can trigger in T lymphocytes caspase-dependent apoptotic
cascades, which are not effectively protected by Bcl-2.
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