Abstract
BackgroundVarious proinflammatory cytokines can be detected within the melanoma tumor microenvironment. Interleukin 32 (IL32) is produced by T cells, NK cells and monocytes/macrophages, but also by a subset of melanoma cells. We sought to better understand the biology of IL32 in human melanoma.MethodsWe analyzed RNA sequencing data from 53 in-house established human melanoma cell lines and 479 melanoma tumors from The Cancer Genome Atlas dataset. We evaluated global gene expression patterns associated with IL32 expression. We also evaluated the impact of proinflammatory molecules TNFα and IFNγ on IL32 expression and dedifferentiation in melanoma cell lines in vitro. In order to study the transcriptional regulation of IL32 in these cell lines, we cloned up to 10.5 kb of the 5′ upstream region of the human IL32 gene into a luciferase reporter vector.ResultsA significant proportion of established human melanoma cell lines express IL32, with its expression being highly correlated with a dedifferentiation genetic signature (high AXL/low MITF). Non IL32-expressing differentiated melanoma cell lines exposed to TNFα or IFNγ can be induced to express the three predominant isoforms (α, β, γ) of IL32. Cis-acting elements within this 5′ upstream region of the human IL32 gene appear to govern both induced and constitutive gene expression. In the tumor microenvironment, IL32 expression is highly correlated with genes related to T cell infiltration, and also positively correlates with high AXL/low MITF dedifferentiated gene signature.ConclusionsExpression of IL32 in human melanoma can be induced by TNFα or IFNγ and correlates with a treatment-resistant dedifferentiated genetic signature. Constitutive and induced expression are regulated, in part, by cis-acting sequences within the 5′ upstream region.
Highlights
Various proinflammatory cytokines can be detected within the melanoma tumor microenvironment
Interleukin 32 (IL32) expression in human melanoma We examined RNA sequencing data from a panel of 53 established human melanoma cell lines derived from resected metastatic deposits [25, 26]
IL32 expression was detectable in a majority of the melanoma cell lines (Fig. 1a)
Summary
Various proinflammatory cytokines can be detected within the melanoma tumor microenvironment. Though first described in 1992 as NK4, interleukin 32 (IL32) [1, 2] was recharacterized in 2005 as a proinflammatory cytokine differentially expressed in IL18 responsive cells. Its expression has been implicated in various pathologies, including rheumatoid arthritis, pathogen responses, atherosclerosis, and several malignancies [3,4,5,6,7,8,9,10,11,12]. Paz et al J Transl Med (2019) 17:113 features associated with worse prognosis, including angiogenesis, invasion, and metastasis [4]. The role of IL32 in human melanoma cells is less well understood. Others reported that IL32 isoforms alpha and gamma were highly enriched in PD-L1 expressing melanoma specimens [23]
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