AntagomiRs targeting miR-146a and miR-21 induce tumor cell death and reinvigorate CD8+ T-cell function in large-cell transformed mycosis fungoides

We previously identified a distinct microRNA (miR) expression profile in LCT-MF with upregulation of miR-21 and miR-146a compared to non-LCT MF. Here, we investigated the efficacy of 2 novel synthesized and chemically modified antagomiRs amiR-146a, and amiR-21 linked to CpG–D19 for delivery on both tumor growth and T cell exhaustion.

Targeting miR-146 and miR-21 alone or combined induced apoptosis through activated caspase 3/7 pathways and caused cell cycle arrest at the G2/M phase via the STAT3/CDK1/Cyclin B1 pathway in CTCL cell lines. In vivo, treatment reduced tumor growth and prolonged survival in mouse xenograft models. CD8+ T cells from LCT-MF patient biopsies exhibited upregulation of immune checkpoint proteins and activation of the STAT3/IRF4/BATF pathway, similar to exhausted CD8+ T cells from healthy donors stimulated to exhaustion in a CTCL culture model.