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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 594-600
Impaired binding of perforin on the surface of tumor cells is a
cause of target cell resistance against cytotoxic effector cells
Christof Lehmann,
Matthias Zeis,
Norbert Schmitz, and
Lutz Uharek
From the Department of Internal Medicine II, University of Kiel,
Kiel, Germany.
Exocytosis of perforin, subsequent binding of perforin to the target
cell membrane, and formation of lytic pores form an important pathway
involved in the induction of tumor cell death by cytotoxic effector
cells. Here we describe a novel escape mechanism employed by tumor
cells to protect themselves from granule-mediated cell death: We were
able to demonstrate that the resistance of the human leukemia cell line
ML-2 to natural killer (NK)-cell-mediated killing is not caused by
impaired NK-cell activation but by resistance against effector
molecules contained in the granules of cytotoxic cells. No resistance
was observed against other pore-forming agents like complement and
streptolysin O. By using the NK-susceptible leukemia cell line K562, we
could show that the induction of cell death by cytotoxic granules can
be blocked completely by anti-perforin antibodies, indicating that
perforin is essentially involved in this process. Flow cytometric data
revealed that an impaired binding of perforin on the tumor cell
membrane is mainly responsible for target cell resistance, because
perforin turned out to bind well on K562 cells but is not able to
attach to the surface of ML-2 cells. After impaired binding of perforin
was identified as a potential mechanism of tumor cell resistance,
leukemia cells from 6 patients with acute myeloid leukemia (AML) were
examined. As predicted, AML cells that failed to bind perforin on their
surface demonstrated complete resistance toward NK-cell-mediated
cytotoxicity. Thus, perforin resistance could represent an important
tumor escape mechanism that should be considered when cytotoxic
effector cells are used for cellular immunotherapy.
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