Alloimmune cells consume interleukin-2 and competitively inhibit the anti-tumour effects of interleukin-2

Abstract

Adoptive immunotherapy with lymphokine activated killer (LAK) cells and recombinant interleukin-2 (IL-2) is successful in a variety of tumour models in both the normal and the immunocompromised mouse. We investigated the effects of an immune response to an allogeneic challenge on the metabolism of IL-2. Serum IL-2 levels at different time points after the administration of 20,000 units of IL-2 intraperitoneally were 2-4 fold higher in normal mice than in recently alloimmunized mice. In an intraperitoneal tumour model the alloimmunization of mice with allogeneic P815 tumour cells or splenocytes IP prior to the intraperitoneal inoculation of syngeneic tumour significantly diminished the anti-tumour effects of IL-2 and LAK cell immunotherapy in 7 consecutive experiments. High doses of IL-2 or pretreatment with cyclophosphamide restored the efficacy of IL-2 and LAK cell immunotherapy. From these results we hypothesize that T cells, activated by the allogeneic challenge, consume IL-2 and thus inhibit the effects of IL-2 and LAK cell treatment by competitive inhibition. LAK cell activity with reduced levels of IL-2 cannot be maintained and anti-tumour effects are lost. High doses of IL-2 were shown to overcome the competition for IL-2. Alternatively activated T-cells could be eliminated by pretreatment with cyclophosphamide and anti-tumour effects restored. These results are important in that they provide an alternative explanation as to the mechanism of non-specific cell mediated suppression and may in part explain the failure of some cancer patients to respond to treatment with IL-2 plus LAK immunotherapy.