Maintenance and cure of the L5178Y murine tumor-dormant state by interleukin 2: Dependence of interleukin 2 on induced interferon-γ and on tumor necrosis factor for its antitumor effects

We reported previously that treatment of peritoneal cell (PC) cultures prepared from mice which harbor L5178Y lymphoma cells in a tumor-dormant state in their peritoneal cavity with interleukin 2 (HuIL-2) stimulated antitumor cytotoxic activity in both the nonadherent and adherent populations derived from such cultures. We report here that HuIL-2 induced the production of murine γ interferon (MuIFN-γ) in these PC cultures and required Lyt-1-, Lyt-2-, and L3T4-expressing lymphocytes to do so. HuIL-2 required and synergized with this induced MuIFN-γ to stimulate cytotoxic activity in the nonadherent PC and the MuIFN-γ itself stimulated cytotoxic activity in the adherent PC. Cyclosporin A prevented both the induction of MuIFN-γ and the development of antitumor cytotoxic activity in HuIL-2-treated PC cultures. An add-back of exogenous MuIFN-γ to HuIL-2-cyclosporin A-treated PC cultures and to the nonadherent subpopulation of such cultures, at a concentration which itself produced no antitumor effect, permitted HuIL-2 to induce its antitumor effect. We previously reported that MuIFN-γ requires the action of murine tumor necrosis factor (MuTNF) to induce cytotoxic activity in PC cultures from tumor-dormant mice. We report here that HuIL-2 also requires the action of (MuTNF) to stimulate antitumor cytotoxic activity in PC cultures from tumor-dormant mice. These results indicate that HuIL-2 induces MuIFN-γ and requires and synergizes with this MuIFN-γ and with (MuTNF) to stimulate antitumor cytotoxic activity in PC cultures from tumor-dormant mice.