Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity.
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.
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Caroline
C
Baer
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Mario Leonardo
ML
Squadrito
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Damya
D
Laoui
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Danielle
D
Thompson
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Sarah K
SK
Hansen
Roche Innovation Center Basel, Pharmaceutical Sciences, Pharma Research and Early Development, 4070 Basel, Switzerland.
Anna
A
Kiialainen
Roche Innovation Center Munich, Oncology Discovery, Pharma Research and Early Development, 82377 Penzberg, Germany.
Sabine
S
Hoves
Roche Innovation Center Munich, Oncology Discovery, Pharma Research and Early Development, 82377 Penzberg, Germany.
Carola H
CH
Ries
Roche Innovation Center Basel, Pharmaceutical Sciences, Pharma Research and Early Development, 4070 Basel, Switzerland.|Roche Innovation Center Munich, Oncology Discovery, Pharma Research and Early Development, 82377 Penzberg, Germany.
Chia-Huey
CH
Ooi
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Michele
M
De Palma
D000818:Animals; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics / Q000276:immunology; D043244:Ribonuclease III / Q000172:deficiency / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000235:genetics*
D035683:MicroRNAs; C542687:mirnlet7 microRNA, mouse; D007371:Interferon-gamma; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases