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Departments of
*
Cell Biology and
Pathology, New York University School of Medicine, New York, NY 10016
Tumor-infiltrating lymphocytes (TIL) are well known to be
functionally impaired typified by the inability to lyse cognate tumor
cells in vitro. We have investigated the basis for defective TIL lytic
function in transplantable murine tumor models. CD8+ TIL
are nonlytic immediately on isolation even though they express surface
activation markers, contain effector phase cytokine mRNAs, and contain
perforin and granzyme B proteins which are packaged into lytic
granules. Ag-specific lytic capability is rapidly recovered if purified
TIL are briefly cultured in vitro and tumor lysis is perforin-, but not
Fas ligand mediated. In response to TCR ligation of nonlytic TIL in
vitro, proximal and distal signaling events are normal; calcium flux is
rapid; mitogen-activated protein/extracellular signal-related kinase
kinase, extracellular regulatory kinase 2, phosphoinositide-3
kinase, and protein kinase C are activated; and IL-2 and IFN-
is
secreted. However, on conjugate formation between nonlytic TIL and
cognate tumor cells in vitro, the microtubule-organizing center (MTOC)
does not localize to the immunological synapse, thereby precluding
exocytosis of preformed lytic granules and accounting for defective TIL
lytic function. Recovery of TCR-mediated, activation-dependent MTOC
mobilization and lytic activity requires proteasome function, implying
the existence of an inhibitor of MTOC mobilization. Our findings show
that the regulated release of TIL cytolytic granules is defective
despite functional TCR-mediated signal
transduction.
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