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

BACKGROUND. Interleukin (IL)-12 can enhance the development of effective im mune responses against tumors as well as against certain infectious agents. It is therefore a potential candidate for therapeutic use in cancer therap y and in design of vaccines against several infectious diseases. METHODS. The authors have established a specific cytotoxic T-cell line (TIL -Heu) from lymphocytes infiltrating a human large cell carcinoma of the lun g (LCC). In the current report, the authors have investigated the in vivo e ffect of recombinant human IL-12 (rhIL-12) on the adoptive transfer of TIL- Heu cells in autologous tumor (Heu-n) engrafted into severe combined immuno deficiency disease-nonobese diabetic (SCID-NOD) mice. RESULTS. Initial in vitro experiments indicated that rhIL-12 increased the cytotoxic potential of TIL-Heu cells in a dose-dependent manner. Heu-n tumo rs transplanted into SCID-NOD mice were injected with TIL-Heu cells, result ing in a significant tumor growth inhibition. When low doses of rhIL-12 wer e 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 grow th. Further in vitro experiments revealed an inhibition of tumor cell lysis after incubation with supernatant of TIL-Heu cells stimulated with high do ses of rhIL-12, strongly suggesting that an immunosuppressive factor secret ed by the high dose IL-12-stimulated CTL may be responsible for the tumor e scape observed in vivo. CONCLUSIONS. 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 resistan ce to CTL killing. Therefore, understanding the cross-talk between immunore gulatory and immunosuppressive cytokines ultimately may provide new approac hes to improve cytokine-mediated cancer immunotherapy. Cancer 2001;91:113-2 2. (C) 2001 American Cancer Society.