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*
Department of Cell Biology and Kaplan Cancer Center, New York University School of Medicine, New York, NY 10016;
Institute of Molecular Genetics and Genetic Engineering, Belgrade, Yugoslavia; and
Second Department of Pathology, Gifu University School of Medicine, Gifu, Japan
Induction of Fas-mediated activation-induced cell death in
antitumor T cells has been hypothesized to permit tumor escape from
immune destruction. Several laboratories have proposed that expression
of Fas ligand (L) by tumor is the basis for this form of T cell
tolerance. In this study, we characterized murine tumor-infiltrating
lymphocytes (TIL) for activation status, cell cycle status, level of
apoptosis, cytokine secretion, and proliferative capacity. TILs express
multiple activation markers (circa CD69, CD95L, CD122, and LFA-1) and
contain IL-2 and IFN-
mRNAs, but are neither cycling nor apoptotic
in situ. In addition, TIL are dramatically suppressed in proliferative
response and do not secrete IL-2 and IFN-. However, upon
purification and activation in vitro, TIL secrete high levels of IL-2
and IFN-, enter S phase, and then die by Fas-mediated apoptosis.
Activation by injection of anti-TCR Ab or IL-2 into tumor-bearing
mice induced TIL entrance into S phase preceding apoptosis, showing
that TIL have functional TCR-mediated signal transduction in situ. Our
data demonstrate that TIL, not tumor, express both Fas and FasL, are
arrested in G1, do not secrete cytokine in situ, and, upon
activation in vitro and in vivo, rapidly die by activation-induced cell
death.
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