Fusion cytokine IL-2-GMCSF enhances anticancer immune responses through promoting cell–cell interactions

Abstract

Background Potent antitumor responses can be induced through cytokine immunotherapy. Interleukin (IL)-2 and granulocyte–macrophage colony-stimulating factor (GM-CSF) are among the most effective cytokines to induce tumor-specific systemic immune responses and can act synergistically. To overcome the limitations of combined use of these two cytokines, we have constructed an IL2-GMCSF fusion protein and characterized its antitumor effects in this study.MethodsThe expression of IL-2 receptor and GM-CSF receptor of cell lines were detected with quantitative real-time PCR. On this basis, the bioactivities of IL2-GMCSF, especially effects on DC2.4 cells were assayed. Another function of IL2-GMCSF—bridge two types of cells—was assessed by cell contact counting and cytotoxicity assays. The anti-tumor activity in vivo of IL2-GMCSF was evaluated in the melanoma model. The statistical significance among treatment groups were determined by One-Way ANOVA.ResultsThe fusion protein IL2-GMCSF maintained the activities of IL-2 and GM-CSF, and could significantly promote DC2.4 cell activities, including phagocytosis, proliferation and cytokine secretion. In addition to the inherent cytokine activity, IL2-GMCSF bridges direct cell–cell interactions and enhances splenocyte killing efficacy against multiple tumor cell lines in vitro. Co-injection of IL2-GMCSF and inactivated B16F10 mouse melanoma cells induced complete immunoprotective responses in about 30 % of mice.ConclusionThese results suggested that IL2-GMCSF can efficiently regulate immune responses against tumors. Furthermore, as the bridging effect relies on both IL-2R and GM-CSFR and promotes interactions between immune and tumor cells, IL2-GMCSF may be utilized as a useful tool for dissecting specific immune responses for future clinical applications.

Immunotherapy against metastatic bladder cancer by combined administration of granulocyte macrophage‐colony stimulating factor and interleukin‐2 surface modified MB49 bladder cancer stem cells vaccine

“…Recently, Wen et al. constructed an IL2‐GMCSF fusion cytokine, which was able to regulate immune responses against tumors efficiently . However, whether combined administration of GM‐CSF and IL‐2 could produce specific immune responses to cancer stem cells (CSCs) was uncertain.…”

(Im)maturity in Tumor Ecosystem

“…Agents act on maturation of anti-tumor immune cells can thus be designed for strengthening the power of the immune system against cancer. IL-2, for instance, promotes maturation of T cells ( 186 ), and it can be a key component of most of the immunotherapeutic approaches ( 187 ) due to its effects on promoting the effector function of cells like macrophages, NK cells, and CD8 + T cells ( 59 ). A point of value here is that even when maturation occurs in a cell like DCs, it may not be sufficient to induce a strong immunity ( 18 ), so agents designed to act on maturation of anti-tumor immune cells must also induce an effector functionality.…”

“…There is a net of functional circuity between NK cells with DCs and CD8 + T cells, which results in a maximized effector function against cancer ( 58 ). Direct cell-to-cell contact between NK cells with DCs promotes immune responses through induction of DC maturation ( 11 , 59 ). Matured DC cells can uptake tumor antigens from secondary lymph nodes.…”

Identification of an immune-related gene signature to improve prognosis prediction of colorectal cancer patients

“…Interleukin (IL) was secreted by a wide range of immune, cancerous or endocrine cells, belong to a sophisticated superfamily that's closely associated with immune cell proliferation, hemostasis regulation, up-or-down regulation of cell activity and expansions during cancerous and in ammation situations [41][42][43] . IL-2 was reported to trigger synergetic cancer-speci c immune reaction at high dose 44 , while IL-10 known as the tolerogenic cytokine which inhibit proin ammatory cytokine production and suppress the stimulation of T cells 45,46 . On the other hand, as part of self-regulating mechanism, immune cells (eg.…”