MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints

Neuro Oncol. 2016 May;18(5):639-48. doi: 10.1093/neuonc/nov292. Epub 2015 Dec 11.


Background: Antibody therapeutic targeting of the immune checkpoints cytotoxic T-lymphocyte-associated molecule 4 (CTLA-4) and programmed cell death 1 (PD-1) has demonstrated marked tumor regression in clinical trials. MicroRNAs (miRNAs) can modulate multiple gene transcripts including possibly more than one immune checkpoint and could be exploited as immune therapeutics.

Methods: Using online miRNA targeting prediction algorithms, we searched for miRNAs that were predicted to target both PD-1 and CTLA-4. MiR-138 emerged as a leading candidate. The effects of miR-138 on CTLA-4 and PD-1 expression and function in T cells were determined and the therapeutic effect of intravenous administration of miR-138 was investigated in both immune-competent and -incompetent murine models of GL261 glioma.

Results: Target binding algorithms predicted that miR-138 could bind the 3' untranslated regions of CTLA-4 and PD-1, which was confirmed with luciferase expression assays. Transfection of human CD4+ T cells with miR-138 suppressed expression of CTLA-4, PD-1, and Forkhead box protein 3 (FoxP3) in transfected human CD4+ T cells. In vivo miR-138 treatment of GL261 gliomas in immune-competent mice demonstrated marked tumor regression, a 43% increase in median survival time (P = .011), and an associated decrease in intratumoral FoxP3+ regulatory T cells, CTLA-4, and PD-1 expression. This treatment effect was lost in nude immune-incompetent mice and with depletion of CD4+ or CD8+ T cells, and miR-138 had no suppressive effect on glioma cells when treated directly at physiological in vivo doses.

Conclusions: MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints which may have rapid translational potential as a novel immunotherapeutic agent.

Keywords: CTLA-4; PD-1; glioblastoma; miR-138; microRNAs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Brain Neoplasms / immunology
  • Brain Neoplasms / pathology*
  • CTLA-4 Antigen / antagonists & inhibitors*
  • CTLA-4 Antigen / immunology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Flow Cytometry
  • Glioma / immunology
  • Glioma / pathology*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • MicroRNAs / pharmacology*
  • Polymerase Chain Reaction
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology


  • Antineoplastic Agents
  • CTLA-4 Antigen
  • MIRN138 microRNA, human
  • MicroRNAs
  • Programmed Cell Death 1 Receptor