C. Lehmann et al., Impaired binding of perforin on the surface of tumor cells is a cause of target cell resistance against cytotoxic effector cells, BLOOD, 96(2), 2000, pp. 594-600
Exocytosis of perforin, subsequent binding of perforin to the target cell m
embrane, and formation of lytic pores form an important pathway involved in
the induction of tumor cell death by cytotoxic effector cells. Here we des
cribe a novel escape mechanism employed by tumor cells to protect themselve
s from granule-mediated cell death: We were able to demonstrate that the re
sistance of the human leukemia cell line ML-2 to natural killer (NK)-cell-m
ediated killing is not caused by impaired NK-cell activation but by resista
nce against effector molecules contained in the granules of cytotoxic cells
. No resistance was observed against other pore-forming agents like complem
ent 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 tha
t an impaired binding of perforin on the tumor cell membrane is mainly resp
onsible for target cell resistance, because perforin turned out to bind wel
l on K562 cells but Is not able to attach to the surface of ML-2 cells. Aft
er impaired binding of perforin was identified as a potential mechanism of
tumor cell resistance, leukemia cells from 6 patients with acute myeloid le
ukemia (AML) were examined. As predicted, AML cells that failed to bind per
forin on their surface demonstrated complete resistance toward NK-cell-medi
ated cytotoxicity. Thus, perforin resistance could represent an important t
umor escape mechanism that should be considered when cytotoxic effector cel
ls are used for cellular immunotherapy. (C) 2000 by The American Society of
Hematology.