T cell-mediated tumor rejection displays diverse dependence upon perforin and IFN-gamma mechanisms that cannot be predicted from in vitro T cell characteristics

Experimental pulmonary metastases have been successfully treated by adoptiv e transfer of tumor-sensitized T tells from perforin knockout (KO) or Fas/A PO-1 ligand(KO) mice, suggesting a prominent role for secretion of cytokine s such as IFN-gamma. In the present study we confirmed that rejection of es tablished methylcholanthrene-205 (MCA-205) pulmonary metastases displayed a requirement for T cell IFN-gamma expression. However, this requirement cou ld be obviated by transferring larger numbers of tumor-sensitized IFN-gamma (KO) T cells or by immunosensitizing sublethal irradiation (500 rad) of th e host before adoptive therapy. Extrapulmonary tumors (MCA-205 s.c. and int racranial) that required adjunct sublethal irradiation for treatment effica cy also displayed no requirement for host or T cell expression of IFN-gamma , Nonetheless, rejection of MCA-205 s.c. tumors and i.p. EL-4 tumors, but n ot MCA-205 pulmonary or intracranial tumors, displayed a significant requir ement for T cell perforin expression (i.e., CTL participation). The capacit y of T cells to lyse tumor targets and secrete IFN-gamma in vitro before ad optive transfer was nonpredictive of the roles of these activities in subse quent tumor rejection, Adoptive therapy studies employing KO mice are there fore indispensable for revealing a diversity of tumor rejection mechanisms that may lark in vitro correlation due to delays In their induction, Seemin gly contradictory KO data from different studies are reconciled by the capa city of anti-tumor T cells to rely on alternative mechanisms when treated i n larger numbers, the variable participation of CTL at different anatomic l ocations of tumor, and the apparent capacity of sublethal irradiation to pr ovide a therapeutic alternative to host or T cell IFN-gamma production.