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Published online before print May 17, 2006

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(Journal of Leukocyte Biology. 2006;80:96-106.)
© 2006 by Society for Leukocyte Biology

Immune phenomena involved in the in vivo regression of fibrosarcoma cells expressing cell-associated IL-1

Tatyana Dvorkin^*, Xiaoping Song^*,1, Shmuel Argov, Rosalyn M. White^*, Margot Zoller, Shraga Segal^*,2, Charles A. Dinarello, Elena Voronov^* and Ron N. Apte^*,3

^* Departments of Microbiology and Immunology and
Pathology, Faculty of Health Sciences and the Cancer Research Center, Ben-Gurion University of the Negev, Beer Sheva, Israel;
Department of Tumor Progression and Tumor Defense, German Cancer Research Center, Heidelberg; and
University of Colorado Health Sciences Center, Denver

³ Correspondence: Department of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. E-mail: rapte{at}bgumail.bgu.ac.il

Constitutive expression of cell-associated, but not secreted, interleukin-1 (IL-1) by oncogene-transformed fibrosarcoma cells induced regressing tumors in mice, a phenomenon that was abrogated by the IL-1 inhibitor, the IL-1 receptor antagonist (IL-1Ra). On the contrary, non-IL-1-expressing tumor cells induce progressive tumors in mice. In vivo and ex vivo experiments have shown that regression of IL-1-positive fibrosarcoma cells depends on CD8⁺ T cells, which can also be activated in CD4⁺ T cell-depleted mice, with some contribution of natural killer cells. In spleens of mice bearing the non-IL-1-expressing fibrosarcoma cells, some early and transient manifestations of antitumor-specific immunity, such as activation of specific proliferating T cells, are evident; however, no development of cytolytic T lymphocytes or other antitumor protective cells could be detected. In spleens of mice bearing the non-IL-1-expressing fibrosarcoma cells, the development of early tumor-mediated suppression was observed, and in spleens of mice injected with IL-1-positive fibrosarcoma cells, protective immunity developed in parallel to tumor regression. Treatment of mice bearing violent fibrosarcoma tumors with syngeneic-inactivated, IL-1-positive fibrosarcoma cells, at a critical interval after injection of the malignant cells (Days 5–12), induced tumor regression, possibly by potentiating and amplifying transient antitumor cell immune responses or by ablation of tumor-mediated suppression. Membrane-associated IL-1 may thus serve as an adhesion molecule, which allows efficient cell-to-cell interactions between the malignant and immune effector cells that bear IL-1Rs and function as a focused cytokine with adjuvant activities at nontoxic, low levels of expression. Our results also point to the potential of using antitumor immunotherapeutic approaches using cell-associated IL-1.

Key Words: interleukin-1 • protective immunity

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