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

Abstract

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.

Host-Derived Interleukin-1α Is Important in Determining the Immunogenicity of 3-Methylcholantrene Tumor Cells

“…Finally, in comparison to effector cells from WT mice, innate and specific antitumor effector cells from IL-1␣ Ϫ/Ϫ mice, i.e., NK cells, LAK cells, and CTL, displayed a reduced killing capacity, which correlated with reduced expression of perforin and granzyme B in purified NK cells from IL-1␣ Ϫ/Ϫ mice. The unique membrane-associated form of IL-1␣ is possibly of importance for its efficiency in activating antitumor immune responses, by acting as a focused adjuvant, through binding to IL-1RI, which are abundant on immunosurveillance cells, as has been demonstrated in our previous studies (24,25,(27)(28)(29)(30)(31). Membrane IL-1␣ may also be important in the effector phase of antitumor immunity, by enabling more avid binding between target tumor cells and immunosurveillance effector cells that leads to better killing.…”

“…Compared with IL-1␤, IL-1␣ is secreted in only a limited manner, especially by macrophages, and thus induces limited inflammatory responses and in its membrane-associated form it is immunostimulatory. Indeed, malignant fibrosarcoma cells which express cell-associated IL-1␣, which acts as a focused adjuvant, exhibit increased immunogenicity and induce regressing tumors in mice, through activation of anti-tumor cell immunity (24,25,(27)(28)(29)(30)(31).…”

Effects of IL-1 molecules on growth patterns of 3-MCA-induced cell lines: An interplay between immunogenicity and invasive potential

“…Using transfectants of fibrosarcoma cells with active forms of the IL-1 molecules, we have shown that IL-1β secreted by malignant cells contributes to increased tumor invasiveness and angiogenesis, as well as to general anergy in the host, mediated by myeloid precursor cells. In contrast, fibrosarcoma cell lines overexpressing IL-1α, mainly on the cell surface or intracellularly, are highly immunogenic and induce regressing tumors, due to eradication of the malignant cells by the host's immune system (Song et al, 2003(Song et al, , 2005Dvorkin et al, 2006).…”

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b+Gr1+ cells in carbon tetrachloride‐induced liver injury in mice

“…In contrast, IL-1α is active as an intracellular precursor (proIL-1α), a membrane form, and as a secreted form (mature form, 18 kDa) [10]. Membrane IL-1α (ß23kDa) is thought to be immunostimulatory [11], while cytosolic proIL-1α controls homeostatic functions, such as gene expression and control of proliferation and differentiation [12]. IL-1α is not secreted and retained in cells during apoptosis process [13].…”

“…On the contrary, the membrane IL-1α even slightly protected the mice from CCl 4 -induced acute liver injury. It has been suggested that membrane IL-1α could function as an adhesion molecular to promote immune responses [11,50]. The mechanism of its protective role in acute liver injury still needs further investigation.…”