Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF‐M and melanocyte differentiation antigens

Abstract

We report that melanoma cell lines expressing the interleukin-1 receptor exhibit 4-to 10-fold lower levels of mRNA of microphthalmia-associated transcription factor (MITF-M) when treated with interleukin-1b. This effect is NF-jB and JNKdependent. MITF-M regulates the expression of melanocyte differentiation genes such as MLANA, tyrosinase and gp100, which encode antigens recognized on melanoma cells by autologous cytolytic T lymphocytes. Accordingly, treating some melanoma cells with IL-1b reduced by 40-100% their ability to activate such antimelanoma cytolytic T lymphocytes. Finally, we observed large amounts of biologically active IL-1a or IL-1b secreted by two melanoma cell lines that did not express MITF-M, suggesting an autocrine MITF-M downregulation. We estimate that~13% of melanoma cell lines are MITF-M-negative and secrete IL-1 cytokines. These results indicate that the repression of melanocyte-differentiation genes by IL-1 produced by stromal cells or by tumor cells themselves may represent an additional mechanism of melanoma immune escape.

Inflammasome polymorphisms confer susceptibility to sporadic malignant melanoma

“…We hypothesize that this gain-of-function SNP because of increased IL-1b levels, might upregulate other related pro-inflammatory genes like TNF-a and NF-jB through a positive feedback loop, which might promote melanoma cells to resist elimination by the T lymphocytes. This survival phenomenon has previously been demonstrated in melanoma cell lines treated with cytokines like TNF-a (Englaro et al, 1999) and very recently IL-1b (Kholmanskikh et al, 2010).…”

Immune Cell–Poor Melanomas Benefit from PD-1 Blockade after Targeted Type I IFN Activation

“…1A and B and Supplementary Table S1). The type I IFN response signature was generated from a publicly available dataset of IFNα-treated human melanoma cells ( 24 ). Furthermore, high expression of type I IFN-responsive genes or CD3D was associated with an increased relapse-free survival, consistent with the idea that preexisting antitumoral immune responses determine a favorable prognosis in patients with melanoma ( Fig.…”

“…The GSE19428 dataset was used to identify a core signature of type I IFNα-induced genes across fi ve human melanoma cell lines (referred to as type I IFN response signature). The gene expression data (GSE19428_series_matrix.txt) were downloaded as normalized data using global scaling with a trimmed mean target intensity of each array set to 100 ( 24 ). Expression data were log 2 -transformed, and the top 50 differentially expressed genes were identifi ed by comparing mean expression values of IFNα-treated cells versus untreated control cells.…”

Effects of human leukocyte antigen (HLA)-DR engagement on melanoma cells

“…JNK is crucial in the regulation of cell proliferation, cell survival, cell death, DNA repair and metabolism and the activation of JNK has been shown to either promote or eradicate tumours depending on the cellular context (45,46). The critical role of this kinase in melanoma growth and progression as well as its role in melanoma immune escape through the repression of melanocytedifferentiation gene expression in cells treated with some inflammatory cytokines has been previously reported (47,48). Taken together, our studies suggest a model in which the stimulation of melanoma cells via MHC class II molecules and the consequent redistribution of class II molecules into areas of lipid raft microdomains, provide foci of signalling that could be useful for melanoma cells to frustrate an effective anti-tumour response as well the activation of JNK thus modulating multiple cell invasion-associated gene expression (49,50).…”