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| Status |
Public on Mar 21, 2023 |
| Title |
Context-dependent activation of STING-interferon signaling by CD11b agonists enhances anti-tumor immunity |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.
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| Overall design |
Immune cells of subcutaneous PDAC Tumor tissue from C57BL/6 mice were isolated by Fluorescence-activated cell sorting (FACS) according to CD45+ staining and analyzed using scRNAseq.
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| Web link |
https://pubmed.ncbi.nlm.nih.gov/37236195/
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| Contributor(s) |
Liu X, Baer J, DeNardo D |
| Citation(s) |
37236195 |
| |
| Submission date |
Dec 14, 2022 |
| Last update date |
Jun 20, 2023 |
| Contact name |
David DeNardo |
| E-mail(s) |
johnbaer@wustl.edu, ddenardo@wustl.edu
|
| Phone |
3143231324
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| Organization name |
Washington University in St. Louis
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| Department |
Internal Medicine
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| Lab |
DeNardo
|
| Street address |
660 S Euclid Ave.
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| City |
St. Louis |
| State/province |
Missouri |
| ZIP/Postal code |
63110 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA912163 |
