CYTOKINE-INDUCED TUMOR IMMUNOGENICITY - ENDOGENOUS INTERLEUKIN-1-ALPHA EXPRESSED BY FIBROSARCOMA CELLS CONFERS REDUCED TUMORIGENICITY

A direct correlation between the constitutive expression of IL-1 alpha and reduced tumorigenicity of fibrosarcomas was observed. This was established in fibrosarcoma cell lines which produce IL-1 alpha 'spontaneously', possibly as an aberration of oncogene-mediated transformation or upon IL-1 alpha 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 tumor regression of the IL-1 alpha-positive fibroblastoid cell lines indicated that IL-1 alpha potentiates the development of tumor cell-specific CTLs, which are of importance for tumor eradication. Thus, IL-1 alpha induces enhanced helper T cell activity which provides auxiliary signals for the growth/development of CTLs. Non-adaptive effector cells, activated locally by IL-1 alpha-expressing fibrosarcoma cells, also contribute 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, thus further potentiating anti-tumor immune responses. Mice, in which IL-1 alpha-producing tumors were regressed, developed an immune memory and rejected a challenge with an IL-1 non-producing violent tumor cell line. Endogenous IL-1 alpha activates a cytokine cascade (i.e., IL-6, CSF), produced by the malignant cells and possibly also by stromal cells. However, IL-1 alpha expression is essential for fibrosarcoma eradication, while other cytokines possibly amplify and sustain its action. IL-1 non-producing fibrosarcomas can be induced to express IL-1 alpha in a transient manner, by treatment in culture with cytokine/LPS, and subsequently they shift from progressor to regressor tumors. Positive immunotherapeutical effects were obtained when treating mice bearing IL-1 non-producing fibrosarcomas with cells from the same line, induced to express IL-1 alpha in a constitutive or transient manner. Thus, IL-1 alpha expression by malignant cells bears the potential to be applied in immunotherapy, as it is assumed that most naturally occurring tumors do not express IL-1 alpha activity. Further studies are aimed at the elucidation of the mechanisms of IL-1 alpha-mediated tumor regression and on the development of immunotherapy protocols based on its expression by malignant cells.