We detected a strong correlation between the constitutive expression of
IL-1 alpha and reduced tumorigenicity, using
fibrosarcomas which produce the
cytokine spontaneously (as an aberration of the transformation process) or upon gene transfer. In fibroblasts intracellular or membrane-associated
IL-1 alpha is expressed, whereas the secreted form of the
cytokine (IL-1 beta) is absent. Studies on the mechanisms of tumour regression of the
IL-1 alpha producing fibroblastoid cell lines indicated that
IL-1 alpha potentiates the development of tumour cell-specific CTLs, which are of importance for tumour eradication. It also appears that
IL-1 alpha-induced enhanced helper T-cell activity provides auxiliary signals for the growth/development of CTLs. In addition, we observed a massive lymphocytic infiltrate in
IL-1 alpha producing regressing tumours which ultimately replaces the tumour's mass. Non-adaptive effector cells, activated locally by
IL-1 alpha expressing
fibrosarcoma cells, were also shown to contribute, to some extent, to the eradication of
IL-1 alpha expressing
fibrosarcomas. Local
IL-1 alpha expression potentiated antigen presentation, by the malignant fibroblasts as well as by tissue-resident antigen-presenting cells, and by this anti-tumour immune responses were further potentiated. Mice, in which
IL-1 alpha producing tumours regressed, developed systemic immunity and rejected a challenge with a non
IL-1 producing violent tumour cell line. It appears that endogenous
IL-1 alpha, being a strong inducer of
cytokine production, operates a whole
cytokine cascade (such as IL-6, CSFs and
prostaglandins). However, studies using clonal populations have indicated that
IL-1 alpha is essential for
fibrosarcoma eradication, whereas the other
cytokines possibly amplify and sustain its action. We assume that most naturally occurring tumours are not constitutive
IL-1 alpha producers, as it would be disadvantageous for the tumour to express a
cytokine which increases its immunogenicity. However,
IL-1 non-producing
fibrosarcomas can be induced easily to express
IL-1 transiently, by treatment with
cytokines/LPS, and upon the induction of the
cytokine they shift from progressor to regressor tumours. We also obtained positive immunotherapeutical effects when treating mice bearing
IL-1 non-producing
fibrosarcomas with cells from the same line induced in vitro to express
IL-1 alpha. The results may shed light on a novel parameter affecting tumour-host interactions, namely
cytokine expression by the tumorous cells, and may provide the basis for new
immunotherapy protocols for
fibrosarcoma management.