Abstract
Interleukin-18 (IL-18) is a cytokine that enhances innate and adaptive immune responses. Although there are conflicting reports about the roles of IL-18 in melanoma progression, the clinical relevance of IL-18 expression has not been comprehensively studied. In this study, we investigated IL-18 expression and its correlation with patient survival and immune cell infiltration in melanoma using cancer gene expression data publicly available through various databases. IL18 mRNA expression was found to be significantly lower in melanoma tissues than normal tissues. Kaplan–Meier survival analysis showed that IL18 expression was positively correlated with patient survival. To investigate the possible mechanisms by which IL18 expression increased patient survival, we then assessed the correlation between IL18 expression and immune cell infiltration levels. Infiltration of various immune cells, especially CD8+ T and natural killer (NK) cells, which are cytolytic effector cells, was significantly increased by IL18 expression. Additionally, the expression levels of two cytolytic molecules including perforin and granzyme B were significantly positively correlated with IL18 expression. Collectively, this study provides the first evidence that IL18 expression has prognostic value for melanoma patient survival and is strongly correlated with CD8+ T and NK cell infiltration, suggesting the role of IL-18 as a biomarker for predicting melanoma prognosis.
Highlights
Interleukin-18 (IL-18) was first discovered as interferon-gamma (IFN-γ) inducing factor in the sera of mice injected with endotoxins [1]
IL18 expression did not have any correlation with tumor purity or immune infiltration in COAD which was used as a negative control (Figure 4d). These results demonstrate that there is a positive correlation between IL18 expression and immune cell infiltration levels in cancer types, such as Skin Cutaneous Melanoma (SKCM), SARC, and BRCA in which IL18 expression level is positively correlated with good prognosis
Mirjacic Martinovic K et al reported that natural killer (NK) cell cytotoxicity was increased in IL-18/IL-12 treated NK cells isolated from patients with malignant melanoma, whereas IL-18 alone did not show those effect [60]
Summary
Interleukin-18 (IL-18) was first discovered as interferon-gamma (IFN-γ) inducing factor in the sera of mice injected with endotoxins [1] It was eventually identified as IL-18 [2], and is currently classified as a member of the IL-1 superfamily cytokine because IL-18 is structurally related to IL-1, especially IL-1β. IL-18 is first synthesized as a 24 kDa precursor, which is cleaved by caspase-1 into an 18 kDa bioactive form and secreted from various cell types including various immune and non-immune cells [3] This cytokine is produced by activated immune cells, such as monocytes, macrophages, dendritic cells (DCs), neutrophils, natural killer (NK) cells, T cells, and B cells [2]. Various types of cancer produce IL-18, and IL-18 induces cell migration, invasion, and proliferation, resulting in increased metastasis and tumor growth [5,6,7]
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