Immune phenomena involved in the in vivo regression of fibrosarcoma cells expressing cell-associated IL-1alpha.
Constitutive expression of cell-associated, but not secreted, interleukin-1alpha (IL-1alpha) 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-1alpha-expressing tumor cells induce progressive tumors in mice. In vivo and ex vivo experiments have shown that regression of IL-1alpha-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-1alpha-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-1alpha-expressing fibrosarcoma cells, the development of early tumor-mediated suppression was observed, and in spleens of mice injected with IL-1alpha-positive fibrosarcoma cells, protective immunity developed in parallel to tumor regression. Treatment of mice bearing violent fibrosarcoma tumors with syngeneic-inactivated, IL-1alpha-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-1alpha 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-1alpha.
Dvorkin
Tatyana
T
Department of Microbiology and Immunology, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Song
Xiaoping
X
Argov
Shmuel
S
White
Rosalyn M
RM
Zoller
Margot
M
Segal
Shraga
S
Dinarello
Charles A
CA
Voronov
Elena
E
Apte
Ron N
RN
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D005354:Fibrosarcoma / Q000276:immunology*; D053582:Interleukin-1alpha / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D009365:Neoplasm Regression, Spontaneous / Q000276:immunology*
D053582:Interleukin-1alpha