Identification of MicroRNA-mRNA Networks in Melanoma and Their Association with PD-1 Checkpoint Blockade Outcomes.

Abstract

Metastatic melanoma is a deadly malignancy with poor outcomes historically. Immuno-oncology (IO) agents, targeting immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1), have revolutionized melanoma treatment and outcomes, achieving significant response rates and remarkable long-term survival. Despite these vast improvements, roughly half of melanoma patients do not achieve long-term clinical benefit from IO therapies and there is an urgent need to understand and mitigate mechanisms of resistance. MicroRNAs are key post-transcriptional regulators of gene expression that regulate many aspects of cancer biology, including immune evasion. We used network analysis to define two core microRNA-mRNA networks in melanoma tissues and cell lines corresponding to 'MITF-low' and 'Keratin' transcriptomic subsets of melanoma. We then evaluated expression of these core microRNAs in pre-PD-1-inhibitor-treated melanoma patients and observed that higher expression of miR-100-5p and miR-125b-5p were associated with significantly improved overall survival. These findings suggest that miR-100-5p and 125b-5p are potential markers of response to PD-1 inhibitors, and further evaluation of these microRNA-mRNA interactions may yield further insight into melanoma resistance to PD-1 inhibitors.

• Authors: Robert A Szczepaniak Sloane, Michael G White, Russell G Witt, Anik Banerjee, Michael A Davies, Guangchun Han, Elizabeth Burton, Nadim Ajami, Julie M Simon, Chantale Bernatchez, Lauren E Haydu, Hussein A Tawbi, Jeffrey E Gershenwald, Emily Keung, Merrick Ross, Jennifer McQuade, Rodabe N Amaria, Khalida Wani, Alexander J Lazar, Scott E Woodman, Linghua Wang, Miles C Andrews, Jennifer A Wargo
• Journal: Cancers (Cancers (Basel)) Vol. 13 Issue 21 (Oct 22 2021) ISSN: 2072-6694 [Print] Switzerland
• PMID: 34771465 (Publication Type: Journal Article)