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University of Pittsburgh Cancer Institute [T. S., G. D., W. G., M. T. L., T. L. W.] and Departments of Pathology [G. D., T. L. W.], Surgery [M. T. L.], and Molecular Biology and Biochemistry [M. T. L.], University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213
Peripheral
blood mononuclear cells (PBMCs) obtained from patients with advanced
melanoma but not from healthy individuals were found to undergo
spontaneous ex vivo apoptosis upon incubation in medium.
PBMCs were evaluated for evidence of apoptosis using Annexin V
binding, caspase-3 activation, and DNA fragmentation (terminal
deoxynucleotidyl transferase-mediated dUTP nick end labeling). PBMCs of
patients with melanoma contained a significantly higher proportion
(P = 0.0027) of spontaneously apoptotic cells than
PBMCs of controls after 24-h incubation in medium alone. The relative
proportion of activated Fas+ and tumor necrosis factor
receptor 1-positive (TNFR1+) PBMCs was significantly higher
in patients with melanoma than that observed in controls. To
demonstrate that the TNF family of receptors and ligands was involved
in this type of apo-ptosis, PBMCs were incubated in the presence of
agonistic anti-Fas antibody (CH-11) or TNF-
. The proportion of terminal deoxynucleotidyl transferase-mediated dUTP nick end
labeling-positive PBMCs undergoing spontaneous apoptosis was found to
be comparable with that induced by CH-11 antibody or TNF-.
Three-color flow cytometry revealed that CD3+
Fas+ T cells were especially sensitive to apoptosis and
were preprogrammed in vivo to die. Apoptosis occurred in
all subsets of PBMCs but was significantly higher
(P = 0.01) in the CD3+ CD8+
T-cell subset in patients relative to controls. In two patients
with melanoma, who responded clinically to dendritic cell-based peptide
vaccines, the proportion of apoptotic T cells was decreased by half
after therapy. In patients who were treated previously with
vaccination-based therapies, levels of T-cell apoptosis were lower than
in the other melanoma patients. The observed accelerated death of T
cells, which are activated and susceptible to apoptosis in patients
with melanoma, may contribute to a rapid turnover of immune cells,
resulting in a decreased immunocompetence.
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