Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity

Nat Cell Biol. 2016 Jul;18(7):790-802. doi: 10.1038/ncb3371. Epub 2016 Jun 13.


Tumour-associated macrophages (TAMs) largely express an alternatively activated (or M2) phenotype, which entails immunosuppressive and tumour-promoting capabilities. Reprogramming TAMs towards a classically activated (M1) phenotype may thwart tumour-associated immunosuppression and unleash anti-tumour immunity. Here we show that conditional deletion of the microRNA (miRNA)-processing enzyme DICER in macrophages prompts M1-like TAM programming, characterized by hyperactive IFN-γ/STAT1 signalling. This rewiring abated the immunosuppressive capacity of TAMs and fostered the recruitment of activated cytotoxic T lymphocytes (CTLs) to the tumours. CTL-derived IFN-γ exacerbated M1 polarization of Dicer1-deficient TAMs and inhibited tumour growth. Remarkably, DICER deficiency in TAMs negated the anti-tumoral effects of macrophage depletion by anti-CSF1R antibodies, and enabled complete tumour eradication by PD1 checkpoint blockade or CD40 agonistic antibodies. Finally, genetic rescue of Let-7 miRNA activity in Dicer1-deficient TAMs partly restored their M2-like phenotype and decreased tumour-infiltrating CTLs. These findings suggest that DICER/Let-7 activity opposes IFN-γ-induced, immunostimulatory M1-like TAM activation, with potential therapeutic implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • DEAD-box RNA Helicases / deficiency
  • DEAD-box RNA Helicases / metabolism*
  • Humans
  • Interferon-gamma / metabolism*
  • Macrophage Activation / immunology*
  • Macrophages / immunology*
  • Mice
  • MicroRNAs / genetics*
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Ribonuclease III / deficiency
  • Ribonuclease III / metabolism*
  • Tumor Microenvironment / genetics*


  • MicroRNAs
  • mirnlet7 microRNA, mouse
  • Interferon-gamma
  • Dicer1 protein, mouse
  • Ribonuclease III
  • DEAD-box RNA Helicases