Mechanisms of gene regulation in melanoma : interleukin-1 strongly reduces expression of MITF,and BORIS is not required for MAGE1 activation
(2011)
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- Authors
- Supervisors
- De Plaen, Etienne
- Abstract
- (en) Modulation of the immune system for therapeutic ends is now increasingly being employed in patients with advanced cutaneous melanoma, a deadly cancer arising from melanocytes. Cancer immunotherapy, which harnesses the protective capacity and specificity of the immune system toward eliminating cancer cells, generally capitalizes on the specific recognition of tumor antigens by cognate CTLs (cytolytic T lymphocytes). This recognition requires efficient presentation of antigenic peptides on the surface of tumor cells. The aim of this thesis was to explore the mechanisms of transcriptional regulation of genes encoding melanoma antigens in order to identify potential strategies to increase their repertoire and the expression levels. A group of CG (cancer-germline) genes uses primarily DNA methylation for transcriptional repression in somatic cells, whereas genome hypomethylation in tumors results in their activation and presentation of relevant antigenic peptides recognized by cognate CTLs. In the first part of this thesis, we explored the potential of protein BORIS (Brother of the Regulator of Imprinted sites) to induce and/or maintain the activation of MAGE-A1 (Melanoma AntiGEn A1) and other CG genes in melanoma cells. BORIS expression on its own was insufficient to produce these effects and hence may not serve as a general means to increase the repertoire of melanoma antigens. The quantitative analysis of BORIS transcripts revealed the expression pattern characteristic to CG genes. BORIS activation in a substantial proportion of melanoma samples indicates the potential for immunotherapeutic targeting of BORIS-derived antigenic peptides. The identity of such peptides remains to be investigated. The second part of this thesis focused on the mechanisms of the transcriptional regulation of MITF-M, the melanocyte-specific isoform of MITF (Microphthalmia-associated transcription factor). MITF-M is a critical transcriptional activator of melanocyte differentiation genes such as MLANA, tyrosinase and gp100, which encode antigenic peptides recognized on melanoma cells by cognate CTLs. The microarray gene expression studies performed at the Brussels Branch of the Ludwig Institute for Cancer Research have revealed the downregulation of melanocyte differentiation genes in melanoma cell lines exposed to inflammatory cytokines. Based on these observations, we assessed the mechanisms of MITF-M repression by IL-1 (interleukin 1) cytokine. This repression, either induced by exposure to recombinant IL-1 or permanent in melanoma cell lines constitutively producing IL-1, appeared to involve the NF-κB (nuclear factor kappa B) and JNK (c-Jun N-terminal kinase) signaling. The expression level of the IL1R1 (IL-1 receptor 1) was determined as an important parameter of IL-1-mediated transcriptional changes observed in melanoma cell lines. The reduced ability of melanoma cell lines treated with IL-1 to activate differentiation antigen-specific CTL clones was mechanistically demonstrated in vitro. Our 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. In conclusion, our study got insight into mechanisms regulating the expression of melanoma antigens and pointed to the impact of genetic and epigenetic changes in melanoma cells on tumor-immune system interactions. The potential of combining immunotherapy with therapeutic strategies targeting particular genetic and epigenetic aberrations in melanoma cells should be further investigated.
- Affiliations
Citations
Kholmanskikh, O. (2011). Mechanisms of gene regulation in melanoma : interleukin-1 strongly reduces expression of MITF,and BORIS is not required for MAGE1 activation. https://hdl.handle.net/2078.5/149780