Reduced tumorigenicity of fibrosarcomas which constitutively generate IL-1 alpha either spontaneously or following IL-1 alpha gene transfer.

Interleukin-1 (IL-1) is a major immunoregulatory/proinflammatory cytokine which also affects fibroblast proliferation and function and therefore it was of interest to investigate whether its constitutive expression influences the in vivo tumorigenic potential of transformed fibroblastoid cell lines. Here we report on a strong correlation between the constitutive expression of IL-1 alpha and reduced tumorigenicity, using various series of oncogene-transformed NIH/3T3-derived cell lines which produce the cytokine spontaneously or upon gene transfer, following transfection with the IL-1 alpha cDNA. Reduced tumorigenicity of the constitutive IL-1 alpha producing cell lines was manifested either by inability to grow in animals or by regressions of initially growing tumors, within 2 to 3 weeks from cell inoculation. In contrast, mice inoculated with non-IL-1-producing cell lines developed progressive tumors which ultimately killed the animals. Clones obtained from a non-IL-1-producing met-transformed cell line shifted from a progressive to a regressive phenotype, following transfection with an IL-1 alpha-encoding gene, inserted into an appropriate expression vector, resulting in constitutive expression of the cytokine. The effects of constitutive IL-1 expression on tumor development were observed both in histocompatible (NFS/N) and partially allogeneic (BALB/c) mice; however, they were more pronounced in the allogeneic environment. Fibrosarcomas which are non-IL-1 producers induced progressive tumors in both strains of mice at the same growth rate. The differences between the growth characteristics of the fibrosarcomas in histocompatible vs. partially allogenic mice suggest that IL-1 exerts adjuvant-like effects which increase the immunogenicity of tumor-cell antigens, and they also argue against the possibility that an IL-1-mediated local non-specific inflammatory response is the major effector mechanism of tumor rejection. Indeed, in subsequent studies we shall report on the importance of specific cellular immune responses, especially cytotoxic T lymphocytes (CTLs), in the eradication of constitutive IL-1-producing fibrosarcomas. Thus, our findings may serve as the basis for novel immunotherapy strategies aimed at the induction of IL-1 expression by cells comprising the neoplasm or alternatively by local application of the cytokine in the vicinity of the tumor.