Circulating immune cell and microRNA in patients with uveal melanoma developing metastatic disease

• The immune response has been implicated in the control of uveal melanoma progression. Epigenetic mechanisms mediated by specific microRNAs regulate immune responses.
• Immune cells and levels of plasma and cellular immune regulatory microRNAs were examined in uveal melanoma patients followed from primary to metastatic diagnosis.
• Changes in immune effector and regulatory cells were associated with changes in circulating levels of immune regulatory microRNAs.
• These results may guide uveal melanoma immunotherapy and biomarker development.

BackgroundThe immune response has been implicated in the control of uveal melanoma progression. Epigenetic mechanisms mediated by specific microRNAs (miRs) regulate immune responses.MethodsBlood was drawn from six patients with uveal melanoma followed from diagnosis, at which time there was no clinical or radiographic evidence of metastasis, until metastasis manifested. Circulating T cell, natural killer (NK), natural killer T (NKT), and myeloid suppressor cell populations were assessed by flow cytometry. CD3+, CD15+, and CD56+ cells were isolated using immunomagnetic beads. Plasma and cellular levels of immune regulatory miRs were determined by quantitative polymerase chain reaction assays.ResultsThe development of metastasis was associated with decreases in circulating CD3−CD56dim NK cells and CD8+ and double-negative CD3+CD56+ NKT cells. ICOS+CD4+FoxP3+ T regulatory cells and CD11b+CD14−CD15+ myeloid suppressor cells increased. Plasma levels of miR-20a, 125b, 146a, 155, 181a, and 223 were higher in the study patients at diagnosis compared to controls. Plasma levels of miR-20a, 125b, 146a, 155, and 223 increased, and miR-181a decreased when metastasis manifested. Alterations in immune regulatory miRs were also observed in CD3+, CD15+, and CD56+ cell populations.ConclusionsThe development of metastasis in uveal melanoma is associated with changes in immune effector and regulatory cells consistent with lessening tumor immune surveillance. These changes are associated with changes in plasma and cellular levels of immune regulatory miRs. The results may help guide uveal melanoma immunotherapy and biomarker development.