|
| Status |
Public on Nov 09, 2022 |
| Title |
Targeted erythrophagocyte reprogramming of Kupffer cells halts cancer immunotherapy associated liver toxicity [Ter119 experiment] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Agonistic CD40 monoclonal antibodies have emerged as promising immunotherapeutic compounds with impressive anti-tumoral effects. However, one of the main limitations of their use in patients is the severe liver necro-hepatitis they can induce. Up to this point, no effective treatment for anti-CD40 liver toxicity that does not hinder anti-tumor efficacy has been found. In the present study , we show that anti-CD40 liver toxicity is dependent on liver macrophages and recruitment of monocytes and neutrophils. We specifically reprogrammed the phenotype of liver macrophages to anti-inflammatory erythrophagocytes by using repeated injection of anti-erythrocyte murine Ter119 (mTer119) antibody. mTer119 administration induced phagocytosis of erythrocytes by liver macrophages and their transformation to Hmoxhigh/Marcohigh/MHC-IIlow erythrophagocytes. mTer119 treatment prevented anti-CD40 induced liver toxic side-effect, with significantly reduced elevation of plasma transaminases level and area of liver necrosis on histology, while preserving the anti-tumoral efficiency of anti-CD40. Our study offers a novel targeted therapeutic approach to treat immune-related liver adverse side effects of immunotherapies.
|
| |
|
| Overall design |
A C57BL/6J mouse was injected with a single injection of murine Ter119 antibody subcutaneously (35 ug) followed by 10 daily injections at lower dose (10 ug). Another C57BL/6J mouse was injected with similar volume of saline solution. At 24 after the last injection, mice were euthanized and their liver digested into a non-parenchymal single-cell suspension. Cells were enriched for macofphages using a mixture of anti-F4/80 and anti-CD11b coated magnetic beads (Anti-Rat IgG Dynabeads), stained with Totalseq B hashtag antibodies (Biolegend) and pooled together at equal cell count before processing for single-cell RNA sequencing (Chromium Single Cell 3' Reagent Kits User Guide (v3.1)).
|
| |
|
| Contributor(s) |
Vallelian F, Pfefferlé M, Dubach I, Schaer DJ |
| Citation(s) |
36593065 |
| |
| Submission date |
May 12, 2022 |
| Last update date |
Jan 13, 2023 |
| Contact name |
Marc Pfefferle |
| E-mail(s) |
marc.pfefferle@uzh.ch
|
| Organization name |
University hospital Zürich (USZ)
|
| Street address |
Wagistrasse 12
|
| City |
Schlieren |
| State/province |
Schweiz |
| ZIP/Postal code |
8952 |
| Country |
Switzerland |
| |
|
| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (2) |
|
| This SubSeries is part of SuperSeries: |
| GSE202918 |
Targeted erythrophagocyte reprogramming of Kupffer cells halts cancer immunotherapy associated liver toxicity |
|
| Relations |
| BioProject |
PRJNA837627 |
