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Series GSE176109 Query DataSets for GSE176109
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
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.
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).
Web link
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
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (5)
GSM5356093 pool1_cd45
GSM5356094 pool2_cd45
GSM5356095 pool3_cd45
BioProject PRJNA734933
SRA SRP322468

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Supplementary file Size Download File type/resource
GSE176109_IRESeYFP.fa.gz 614 b (ftp)(http) FA
GSE176109_RAW.tar 24.8 Mb (http)(custom) TAR (of TSV)
GSE176109_library_barcodes.csv.gz 144.4 Kb (ftp)(http) CSV
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Raw data are available in SRA
Processed data provided as supplementary file

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