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Mechanisms That Cannot Be Predicted From In Vitro T Cell Characteristics1
Center for Surgery Research, Cleveland Clinic Foundation, Cleveland, OH 44195
Experimental pulmonary metastases have been successfully treated by
adoptive transfer of tumor-sensitized T cells from perforin knockout
(KO) or Fas/APO-1 ligandKO mice, suggesting a prominent
role for secretion of cytokines such as IFN-
. In the present study
we confirmed that rejection of established methylcholanthrene-205
(MCA-205) pulmonary metastases displayed a requirement for T cell
IFN- expression. However, this requirement could be obviated by
transferring larger numbers of tumor-sensitized IFN- KO
T cells or by immunosensitizing sublethal irradiation (500 rad) of the
host before adoptive therapy. Extrapulmonary tumors (MCA-205 s.c. and
intracranial) that required adjunct sublethal irradiation for treatment
efficacy also displayed no requirement for host or T cell expression of
IFN-. Nonetheless, rejection of MCA-205 s.c. tumors and i.p. EL-4
tumors, but not MCA-205 pulmonary or intracranial tumors, displayed a
significant requirement for T cell perforin expression (i.e., CTL
participation). The capacity of T cells to lyse tumor targets and
secrete IFN- in vitro before adoptive transfer was nonpredictive of
the roles of these activities in subsequent tumor rejection. Adoptive
therapy studies employing KO mice are therefore indispensable for
revealing a diversity of tumor rejection mechanisms that may lack in
vitro correlation due to delays in their induction. Seemingly
contradictory KO data from different studies are reconciled by the
capacity of anti-tumor T cells to rely on alternative mechanisms
when treated in larger numbers, the variable participation of CTL at
different anatomic locations of tumor, and the apparent capacity of
sublethal irradiation to provide a therapeutic alternative to host or T
cell IFN- production.
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