Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity
| Autor: | Carola Ries, Danielle Thompson, Sabine Hoves, Sarah K. Hansen, Michele De Palma, Mario Leonardo Squadrito, Caroline Baer, Anna Kiialainen, Chia Huey Ooi, Damya Laoui |
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| Přispěvatelé: | Department of Bio-engineering Sciences, Cellular and Molecular Immunology |
| Rok vydání: | 2016 |
| Předmět: |
Ribonuclease III
0301 basic medicine medicine.medical_treatment macrophage Tumor-associated macrophage Biology DEAD-box RNA Helicases Interferon-gamma Mice tumor-associated macrophage 03 medical and health sciences stomatognathic system Neoplasms PD-1 microRNA Tumor Microenvironment CD40 medicine Animals Humans Macrophage Cytotoxic T cell STAT1 skin and connective tissue diseases Cells Cultured Macrophages Cell Biology Immunotherapy Macrophage Activation DICER Cell biology Let-7 MicroRNAs 030104 developmental biology biology.protein Cancer research immunotherapy macrophage reprogramming hormones hormone substitutes and hormone antagonists Dicer |
| Zdroj: | Nature Cell Biology |
| ISSN: | 1476-4679 1465-7392 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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