?-Interferon Plays a Key Role in T-Cell-induced Tumor Regression

Recent studies have demonstrated that noncytolytic T-cells can mediate regression of murine tumors. In this report, we demonstrate that MCA-105 tumor-draining lymph node cells (DLN) activated with the protein kinase C activator, bryostatin 1, plus a calcium ionophore are capable of inducing specific tumor regression in vivo when adoptively transferred to mice with established metastases. However, these activated DLN cells lack in vitro cytotoxicity against autologous tumor. Antibody against ?-lnterferon (IFN-?) markedly inhibited the therapeutic efficacy of these activated DLN cells. Anti-tumor necrosis factor produced a statistically significant but weaker inhibition of tumor regression. IFN-?, but not tumor necrosis factor a, could be shown to be secreted by activated DLN cells in vitro in response to specific tumor. Secretion of IFN-? was primarily a function of CD8+ T-cells. IFN-? was not directly cytotoxic to sarcoma cells in vitro. Moreover, tumor cells incubated with IFN-? were not more susceptible to lysis by activated DLN cells. However, recombinant murine IFN-? had a significant antiproliferative effect against MCA-105 tumor cells when tested in a [3H]thymidine uptake assay. Similarly, supernatants obtained from DLN/autologous tumor cocultures markedly inhibited MCA-105 proliferation; this antiproliferative effect was abrogated by the addition of anti-IFN-? antibody to the cultures. These results suggest that secretion of IFN-? by adoptively transferred DLN cells plays an essential role in tumor rejection. The dominant effect of IFN-? may be its demonstrated antiproliferative activity.