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| Status |
Public on Jun 04, 2021 |
| Title |
Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Immunotherapy is revolutionizing cancer treatment, but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions remains poorly understood. Here, using anti-CD40-treatment in mice as a model of Th1-promoting immunotherapy, we show liver macrophages’ vulnerability to promote local adverse events. Mechanistically, tissue-resident Kupffer cells mediate liver toxicity by sensing lymphocyte-derived IFN-g and producing IL-12. Conversely, dendritic cells are dispensable for toxicity but drive tumor control. Though macrophages, IL-12, and IFN-g are not necessarily toxic themselves, we find that they prompt a neutrophil response that determines the severity of tissue damage. We further show that similar inflammatory pathways characterize adverse events across tissues, following anti-PD-1 and anti-CTLA4 immunotherapies, and in humans. These findings implicate macrophages and neutrophils as mediators and effectors of aberrant inflammation in Th1-promoting immunotherapy, and suggest distinct mechanisms of toxicity and antitumor immunity.
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| Overall design |
Single cell RNA sequencing (scRNAseq) of CD45-sorted and IL-12p40-EYFP-sorted cells from tumor and liver of IL-12p40-IRES-EYFP reporter mice that were treated or not with agonist anti-CD40 immunotherapy. CD45+ cells were sorted from untreated (n=2) and anti-CD40-treated (n=2) livers; IL-12p40-EYFP+ cells were sorted from anti-CD40-treated liver (n=2) and tumor (n=3).
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| Web link |
https://www.science.org/doi/10.1126/sciimmunol.abi7083
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| Contributor(s) |
Siwicki M, Gort-Freitas NA, Messemaker M, Engblom C, Zilionis R, Klein AM, Pittet MJ |
| Citation(s) |
34215680 |
| |
| Submission date |
Jun 03, 2021 |
| Last update date |
Nov 18, 2021 |
| Contact name |
Nicolas Alejandro Gort-Freitas |
| Organization name |
Harvard Medical School
|
| Department |
Systems Biology
|
| Lab |
Allon Klein
|
| Street address |
200 Longwood Ave
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (5)
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| Relations |
| BioProject |
PRJNA734933 |
| SRA |
SRP322468 |
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