Differential effect of high doses versus low doses of interleukin-12 on the adoptive transfer of human specific cytotoxic T lymphocyte in autologous lung tumors engrafted into severe combined immunodeficiency disease-nonobese diabetic mice: relation with interleukin-10 induction.

Abstract

Interleukin (IL)-12 can enhance the development of effective immune responses against tumors as well as against certain infectious agents. It is therefore a potential candidate for therapeutic use in cancer therapy and in design of vaccines against several infectious diseases. The authors have established a specific cytotoxic T-cell line (TIL-Heu) from lymphocytes infiltrating a human large cell carcinoma of the lung (LCC). In the current report, the authors have investigated the in vivo effect of recombinant human IL-12 (rhIL-12) on the adoptive transfer of TIL-Heu cells in autologous tumor (Heu-n) engrafted into severe combined immunodeficiency disease-nonobese diabetic (SCID-NOD) mice. Initial in vitro experiments indicated that rhIL-12 increased the cytotoxic potential of TIL-Heu cells in a dose-dependent manner. Heu-n tumors transplanted into SCID-NOD mice were injected with TIL-Heu cells, resulting in a significant tumor growth inhibition. When low doses of rhIL-12 were injected intratumorally after TIL-Heu transfer, a clear increase in tumor growth suppression was observed. Surprisingly, higher doses of rhIL-12 had no effect on cytotoxic T lymphocyte (CTL)-induced prevention of tumor growth. Further in vitro experiments revealed an inhibition of tumor cell lysis after incubation with supernatant of TIL-Heu cells stimulated with high doses of rhIL-12, strongly suggesting that an immunosuppressive factor secreted by the high dose IL-12-stimulated CTL may be responsible for the tumor escape observed in vivo. The authors' data indicate that IL-10 may play a critical role in the lack of effect of high dose IL-12, by mediating tumor cell resistance to CTL killing. Therefore, understanding the cross-talk between immunoregulatory and immunosuppressive cytokines ultimately may provide new approaches to improve cytokine-mediated cancer immunotherapy.