Immune phenomena involved in the in vivo regression of fibrosarcoma cells expressing cell-associated IL-1α

Constitutive expression of cell-associ- ated, but not secreted, interleukin-1 (IL-1 )b y oncogene-transformed fibrosarcoma cells in- duced regressing tumors in mice, a phenomenon that was abrogated by the IL-1 inhibitor, the IL-1 receptor antagonist (IL-1Ra). On the contrary, non-IL-1-expressing tumor cells induce pro- gressive tumors in mice. In vivo and ex vivo experiments have shown that regression of IL- 1-positive fibrosarcoma cells depends on CD8 T cells, which can also be activated in CD4 T cell-depleted mice, with some contribution of natural killer cells. In spleens of mice bearing the non-IL-1-expressing fibrosarcoma cells, some early and transient manifestations of antitumor- specific immunity, such as activation of specific proliferating T cells, are evident; however, no development of cytolytic T lymphocytes or other antitumor protective cells could be detected. In spleens of mice bearing the non-IL-1-express- ing fibrosarcoma cells, the development of early tumor-mediated suppression was observed, and in spleens of mice injected with IL-1-positive fibrosarcoma cells, protective immunity devel- oped in parallel to tumor regression. Treatment of mice bearing violent fibrosarcoma tumors with syngeneic-inactivated, IL-1-positive fibrosar- coma cells, at a critical interval after injection of the malignant cells (Days 5-12), induced tumor regression, possibly by potentiating and amplify- ing transient antitumor cell immune responses or by ablation of tumor-mediated suppression. Membrane-associated IL-1 may thus serve as an adhesion molecule, which allows efficient cell-to- cell interactions between the malignant and im- mune effector cells that bear IL-1Rs and func- tion as a focused cytokine with adjuvant activities at nontoxic, low levels of expression. Our results also point to the potential of using antitumor immunotherapeutic approaches using cell-asso- ciated IL-1. J. Leukoc. Biol. 80: 96-106; 2006.