Involvement of immune responses in the eradication of IL-1 alpha gene-transduced tumour cells: mechanisms of tumour rejection and immunotherapeutical implications.
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.
Apte
R N
RN
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva.
Douvdevani
A
A
Zoller
M
M
White
R M
RM
Dvorkin
T
T
Shimoni
N
N
Huleihel
M
M
Fima
E
E
Hacham
M
M
Voronov
E
E
D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D015870:Gene Expression / Q000276:immunology*; D006084:Graft Rejection; D007167:Immunotherapy; D007375:Interleukin-1 / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014162:Transfection
D007375:Interleukin-1