RESUMO
RAGE is a central driver of tumorigenesis by sustaining an inflammatory tumor microenvironment. This study links the soluble forms of RAGE (sRAGE and esRAGE) with clinical outcome of melanoma patients. Moreover, tissue expression of RAGE was analyzed using immunohistochemistry on two independent tissue microarrays (TMA) containing 35 or 257 primary melanomas, and 41 or 22 benign nevi, respectively. Serum concentrations of sRAGE and esRAGE were measured in 229 Stage III-IV patients using ELISA and plasma concentrations of sRAGE were analyzed in an independent second cohort with 173 samples of Stage I-IV patients. In this cohort, three well-described SNPs in the RAGE gene were analyzed. RAGE protein expression was highly upregulated in primary melanomas compared to benign nevi in the two TMA (p < 0.001 and p = 0.005) as well as in sun-exposed melanomas (p = 0.046). sRAGE and esRAGE were identified as prognostic markers for survival as diminished sRAGE (p = 0.034) and esRAGE (p = 0.012) serum levels correlated with poor overall survival (OS). Multivariate Cox regression analysis showed that diminished serum sRAGE was independently associated with poor survival (p = 0.009). Moreover, diminished sRAGE was strongly associated with impaired OS in the second cohort (p < 0.001). Multivariate Cox regression analysis including the investigated SNPs revealed an independent correlation of the two interacting promoter SNPs with impaired OS. In conclusion, the soluble forms of RAGE and variants in its genetic locus are prognostic markers for survival in melanoma patients with high risk for progression.
Assuntos
Melanoma/genética , Melanoma/patologia , Receptor para Produtos Finais de Glicação Avançada/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Regiões Promotoras Genéticas/genética , Regulação para Cima/genética , Adulto JovemRESUMO
As melanoma is an immunogenic tumor, immunotherapy has been investigated as a possible treatment modality for melanoma patients at high risk of relapse and those with metastatic disease. In the past decade progress has been made, ranging from rather nonspecific stimulations of the immune system with IL-2 and IFN-alpha to more specific approaches based on vaccination with tumor antigens. Owing to their unique features, dendritic cells (DCs) represent an important tool for tumor antigen-specific immunotherapy. However, clinical vaccination trials with DCs showed sobering results with respect to objective responses and improvement of overall survival. In this review, principles and methods of DC-based vaccination are presented. Mechanisms impairing clinically successful vaccination strategies are described. Finally, we will discuss perspectives for future developments of DC-based vaccines that might lead melanoma treatment to a new era.