Studying the impact of miR-451 on MIF-induced immunosuppression in metastatic melanoma

Abstract

Cutaneous melanoma is an immunogenic malignancy. Spontaneous regression of melanoma by an effective antitumor immune response can occur occasionally. More frequently, however, key driver mutations are important to support melanoma progression and resistance to immune protection. The genetic instability of melanoma may trigger the expression of several immunosuppressive factors that help melanoma to overcome immunosurveillance. One of these factors is the macrophage migration inhibitory factor (MIF), which plays a critical role in inducing a tolerogenic phenotype in the tumor microenvironment. Recently, we found that targeting MIF interaction with its receptor CD74, is an important strategy for adjuvant cancer immunotherapy. In addition, MIF may bind to other receptors exerting an immunomodulatory response. Targeting MIF expression and signaling activity rather than its receptors on immune cells might be a promising strategy to create novel adjuvant immunotherapies. The miR-451 is a micro RNA that disturbs the expression of MIF. Previous work has shown that downregulating MIF expression by use of miR-451 triggers various effects on several solid tumors. The impact, however, of miR-451 in restoring the antitumor immune response in metastatic melanoma has not been investigated. The present work aims at determining the effects of miR-451 on MIF expression and signaling in the context of metastatic melanoma development. Maintenance of an effective antitumor immune response will also be evaluated. The uncovering of new pre-clinical theurapeutic methods using miRs to effectively target the tumor microenvironment, is of critical importance to develop new adjuvant therapies to increase immunotherapy efficacy and reduce recurrences in melanoma patients.