Abstract
Sentinel node biopsy (SNB) is a main staging biomarker in melanoma and is the first lymph node to drain the tumor, thus representing the immunological site where anti-tumor immune dysfunction is established and where potential prognostic immune markers can be identified. Here we analyzed microRNA (miR) profiles in archival tumor-positive SNBs derived from melanoma patients with different outcomes and performed an integrated analysis of transcriptional data to identify deregulated immune signaling networks. Twenty-six miRs were differentially expressed in melanoma-positive SNB samples between patients with disease progression and non-progressing patients, the majority being previously reported in the regulation of immune responses. A significant variation in miR expression levels was confirmed in an independent set of SNB samples. Integrated information from genome-wide transcriptional profiles and in vitro assessment in immune cells led to the identification of miRs associated with the regulation of the TNF receptor superfamily member 8 (TNFRSF8) gene encoding the CD30 receptor, a marker increased in lymphocytes of melanoma patients with progressive disease. These findings indicate that miRs are involved in the regulation of pathways leading to immune dysfunction in the sentinel node and may provide valuable markers for developing prognostic molecular signatures for the identification of stage III melanoma patients at risk of recurrence.
Highlights
In cutaneous melanoma, sentinel node biopsy (SNB) is the standard clinical practice for intermediate thickness melanoma, providing important staging information for stratifying metastaticGenes 2016, 7, 124; doi:10.3390/genes7120124 www.mdpi.com/journal/genesGenes 2016, 7, 124 risk and for programming adjuvant treatments [1]
Confirmation is emerging in the setting of response to immunotherapy and to targeted profiles in primary tumors and in regional metastases are positively associated with drugs, prognosis indicating that immune signatures may be predictive of response to treatment
We have recently observed that the transcriptional profiles of SNB of stage III patients distinguish melanoma patients with progressive disease [8], suggesting that the immunological setting in the SNB may anticipate the conditions of systemic immunity and provide prognostic information
Summary
Sentinel node biopsy (SNB) is the standard clinical practice for intermediate thickness melanoma, providing important staging information for stratifying metastaticGenes 2016, 7, 124; doi:10.3390/genes7120124 www.mdpi.com/journal/genesGenes 2016, 7, 124 risk and for programming adjuvant treatments [1]. Sentinel node biopsy (SNB) is the standard clinical practice for intermediate thickness melanoma, providing important staging information for stratifying metastatic. SNB positivity upstages a patient to stage III disease, characterized by a highly variable five-year survival rate (78%, 59% and 40% for substages A, Band C, respectively) and defined by the extent of lymph node involvement and the characteristics of the primary tumor [2]. New prognostic markers able to improve the identification of patients at high risk for disease recurrence are critically needed even more today that effective therapies for metastatic melanoma have been developed. Beyond its value as a staging biomarker, the sentinel node directly drains the tumor and represents the first immunological site where dysfunctions of anti-tumor immune response are established and where potential prognostic markers can be identified. MiRs have been shown to condition the tumor microenvironment to a protumorigenic milieu by modulating secretion of cytokines and the expression of costimulatory molecules [6,7]
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