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*
Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany; and
Institute for Pathology, University of Ulm, Ulm, Germany
CD95 (APO-/Fas) ligand (CD95L) is a member of the TNF family
predominantly expressed by activated T and NK cells but also by tumors
of diverse cellular origin. CD95L trimerizes surface CD95 expressed by
target cells that subsequently undergo apoptosis. The role of the
CD95/CD95L system in the down-regulation of an immune response
(activation-induced cell death) is established. However, it is so far
unclear why tumors express CD95L. To investigate whether tumors use the
CD95L to down-regulate an anti-tumor immune response, we
established a transgenic (tg) mouse model consisting of 1)
apoptosis-resistant tumor cells, designated LKC-CD95L, which express
functional CD95L and the model tumor Ag Kb; and 2) perforin
knockout (PKO) anti-Kb TCR tg mice. L1210-Fas antisense
expressing Kb, crmA, and CD95L (LKC-CD95L) killed
CD95+ unrelated tumor targets and Con A-activated
splenocytes from anti-Kb TCR tg PKO mice by a
CD95L-dependent mechanism in vitro. However, we could not detect any
cytotoxic activity against anti-tumor (anti-Kb) T
cells in vivo. We also observed reduced growth of LKC-CD95L in nude
mice and rapid rejection in anti-Kb TCR tg PKO mice.
Because the tumor cells are resistant to CD95L-, TNF-
-, and
TNF-related apoptosis-inducing ligand-induced apoptosis and the mice
used are perforin-deficient, the involvement of these four cytotoxicity
mechanisms in tumor rejection can be excluded. The histological
examination of tumors grown in nude mice showed infiltration of
LKC-CD95L tumors by neutrophils, whereas L1210-Fas antisense expressing
Kb and crmA (LKC) tumor tissue was neutrophil-free.
Chemotaxis experiments revealed that CD95L has no direct
neutrophil-attractive activity. Therefore, we conclude that LKC-CD95L
cells used an indirect mechanism to attract neutrophils that may cause
tumor rejection.
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