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Published online before print May 17, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0905509

Received for publication September 11, 2005.
Revised February 5, 2006.
Accepted for publication February 22, 2006.

Article

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

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

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

^@ To whom correspondence should be addressed. E-mail: rapte{at}bgumail.bgu.ac.il.

	Abstract

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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