Induction of antitumor immunity by indomethacin

Irradiated tumor cells given, together with indomethacin, to syngeneic mice induced an antitumor response and conferred protection against a challenge of a lethal dose of murine mammary (4T1) and lung (3LL) carcinoma cells. C ontinuous administration of indomethacin was crucial throughout the entire period of immunization and challenge, as no protection was achieved when th e drug was given during only one of these procedures. Antitumor immunity wa s long-lasting and, when tested in the 4T1 model, 48% of mice were resistan t to a second challenge of lethal tumor cells. Tumor-free immune mice that were given indomethacin for more than 300 days remained healthy with normal white blood cell counts and normal spleen size. Cells isolated from immune mice were able to kill tumor cells in culture after in vitro activation by interleukin-2, in a manner similar to cells from naive normal control mice . In addition, the mito-genic response of their T cells was as high as that of the control naive mice. While indomethacin was able to induce antitumor immunity to 4T1 and 3LL murine carcinoma cells, both of which contain a hi gh concentration of endogenic prostaglandin E-2 (PGE2), no such immunity wa s achieved to murine tumor cells with a low concentration of endogenic PGE2 . These results suggest a correlation between PGE2 concentration and the ab ility of indomethacin to induce antitumor immunity. We therefore suggest th at an immunotherapy protocol with long-term dispensation of a tolerable dos e of an immunomodulator, given together with irradiated autologous tumor ce lls, may stimulate antitumor responses to tumors containing high concentrat ions of endogenic PGE2.