Opposing effects of fibrosarcoma cell-derived IL-1 alpha and IL-1 beta on immune response induction.
There is evidence that cell-associated IL-1 alpha supports immune response induction. Here we explored the impact of malignant cell-derived IL-1 on immunogenicity, immune response induction and tumor-induced immunosuppression using 3-methylcholanthrene-induced fibrosarcoma lines derived from wild-type (wt), IL-1 alpha-, IL-1 beta- or IL-1a beta-knockout (IL-1 alpha(-/-), IL-1 beta(-/-), IL-1 alphabeta(-/-)) C57BL6 mice. The wt, IL-1 alpha(-/-), IL-1 beta(-/-) and IL-1 alphabeta(-/-) fibrosarcoma lines express MHC class I molecules at a high level. The lines do not differ in their susceptibility toward NK cells, macrophages, and allogeneic CTL, or in their capacity as stimulators of an allogeneic response. However, IL-1 beta(-/-) tumors rarely grow in the syngeneic host, which is the consequence of a strong T helper and CTL response induction by IL-1 alpha-competent, IL-1 beta(-/-) tumors. On the other hand, IL-1 beta-competent, IL-1 alpha(-/-) tumors strongly assist CD11b(+)Gr-1(+) myeloid-derived suppressor cell and regulatory T cell expansion, which both suppress with high efficacy activated T helper cell proliferation and CTL lysis. In IL-1 alphabeta(-/-) tumors, the absence of IL-1 alpha becomes decisive, i.e. despite reduced suppressor cell recruitment, tumor growth was unimpaired due to inefficient immune response induction. Thus, sarcoma cell-derived IL-1 alpha and IL-1 beta do not act in concert. Induction of a strong immune response by IL-1 alpha demands therapeutic exploitation, which may become more efficient if systemic induction of immunosuppression by IL-1 beta can also be circumvented.
Marhaba
Rachid
R
Department of Tumor Progression and Tumor Defense, German Cancer Research Center, Heidelberg, Germany.
Nazarenko
Irina
I
Knöfler
Daniela
D
Reich
Eli
E
Voronov
Elena
E
Vitacolonna
Mario
M
Hildebrand
Dagmar
D
Elter
Elena
E
Apte
Ron N
RN
Zöller
Margot
M
D000818:Animals; D005354:Fibrosarcoma / Q000139:chemically induced / Q000276:immunology*; D005434:Flow Cytometry; D007108:Immune Tolerance; D053582:Interleukin-1alpha / Q000276:immunology* / Q000494:pharmacology; D053583:Interleukin-1beta / Q000276:immunology* / Q000494:pharmacology; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D013047:Specific Pathogen-Free Organisms; D013602:T-Lymphocytes, Cytotoxic; D014407:Tumor Cells, Cultured
D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D008748:Methylcholanthrene