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| Status |
Public on Jun 13, 2016 |
| Title |
DICER controls macrophage polarization and tumor response to immunotherapy |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Tumor-associated macrophages (TAMs) have immunosuppressive capacity in mouse models of cancer. Here we show that the genetic deletion of the microRNA (miRNA)-processing enzyme DICER in TAMs broadly programs them to a CD11c+MRC1−/low M1-like immunostimulatory phenotype characterized by activated interferon-γ (IFN-γ)/STAT1/IRF signaling. M1-like TAM programming fostered the recruitment of cytotoxic T-cells (CTLs), including tumor-antigen-specific CTLs, inhibited tumor growth, and enhanced the efficacy of PD1 checkpoint blockade. Bioinformatics analysis of TAM transcriptomes identified a limited set of miRNAs putatively involved in TAM programming. Re-expression of Let-7 in Dicer-deficient TAMs was sufficient to partly rescue the M2-like (protumoral) TAM phenotype and abate tumor CTL infiltration. Targeted suppression of DICER activity in TAMs may, therefore, stimulate antitumor immunity and enhance the efficacy of cancer immunotherapy.
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| Overall design |
To explore the role of DICER in the development, activation and immunological functions of TAMs, we crossed homozygous LysM-Cre (Clausen et al., 1999) with Dicerlox/lox (Harfe et al., 2005) mice to obtain mice with myeloid-cell-specific Dicer1 gene deletion (LysM-Cre;Dicer–/–, referred to as D–/–). These mice were then backcrossed to LysM-Cre to obtain the control LysM-Cre; Dicer+/+ mice (referred to as D+/+). Both LysM-Cre and Dicerlox/lox mutations were always homozygous in our experiment. We then inoculated Lewis lung carcinoma (LLC) cells subcutaneously (s.c.) in D–/– and control D+/+ mice. Once the tumors were established, we isolated by fluorescence-activated cell sorting (FACS) tumor-associated macrophages (F4/80+ cells).
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| Contributor(s) |
De Palma M, Ooi C |
| Citation(s) |
27295554 |
| |
| Submission date |
Dec 28, 2015 |
| Last update date |
May 15, 2019 |
| Contact name |
Chia-Huey Ooi |
| Organization name |
F. Hoffmann-La Roche Ltd.
|
| Street address |
Grenzacherstrasse 124
|
| City |
Basel |
| ZIP/Postal code |
4070 |
| Country |
Switzerland |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA307086 |
| SRA |
SRP067829 |
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