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Zhu Lab, Stanford Cardiovascular Institute"],"full_dataset_link":["https://www.ebi.ac.uk/ena/browser/view/PRJNA1051857"],"scientific_name":["Mus musculus"],"tag":["xref:PubMed:39931812"],"long_description":["Immune checkpoint inhibitors (ICIs) are effective against many cancers but can also cause immune-related adverse events. Although rare, ICI-mediated myocarditis has a high fatality rate of up to 40% and is also associated with heart failure and life-threatening arrhythmias. We characterized a population of CXCL9+CXCL10+ macrophages and CXCR3hi CD8+ T-cells in the hearts of mice with myocarditis and elucidated chemokine crosstalk between the CXCR3hi CD8+ effector T-cells and the CXCL9+CXCL10+ macrophages in the heart. Depletion of macrophages or blockade of CXCR3 both resulted in significantly decreased immune cell infiltration in the hearts of mice. Similarly, CXCR3 blockade decreased immune cell infiltration into the heart,, thus posing CXCR3 and its ligands as an attractive therapeutic target. Additionally, an in vitro transwell assay showed that selective blockade of CXCR3 and its ligand CXCL10 significantly decreased CD8+ T-cell migration towards macrophages, implicating this interaction in T-cell cardiotropism towards cardiac macrophages. These findings were compared with cardiac biopsies from patients with ICI myocarditis that also demonstrated infiltrating CXCR3+ lymphocytes and CXCL9+/CXCL10+ macrophages. In both mouse cardiac immune cells and patient peripheral blood immune cells, T-cell receptor (TCR)-sequencing revealed expanded TCRs that correlated with CXCR3hi CD8+ T-cells. The identification of a CXCR3-specific T-cell and macrophage interaction as important in the pathogenesis of ICI myocarditis offers a new potential target for a chemokine/chemokine receptor inhibition-focused form of therapy in this disease. Overall design: Here, we used a genetic mouse model of PD-1 deletion combined with a novel pharmacological mouse model of anti-PD1 and anti-CTLA-4 monoclonal antibody treatment on a Murphy Roths Large (MRL) background to model ICI myocarditis. We performed single-cell RNA-sequencing (scRNAseq), single-cell TCR-sequencing (scTCRseq), and CITE-sequencing on immune cells isolated from MRL and MRL/Pdcd1-/- mice at serial timepoints 1, 2, 4 weeks of age. We depleted macrophages from MRL/Pdcd1-/- mice to study the role of macrophages in ICI myocarditis. Subsequently, we inhibited a key chemokine receptor, CXC chemokine receptor 3 (CXCR3), in MRL pharmacologic mouse to assess for reduction in myocarditis. Subsequently, we studied CXCL9/10-CXCR3 interactions between macrophages/T-cells in a transwell assay. Finally, we correlated the results in human single-cell multi-omics data from blood and heart biopsy data. We analyzed immune cell populations in time point data, clodronate macrophage depletion data, and CXCR3 inhibition in a novel pharmacologic mouse model. We study mechanistic relationships between T-cells and macrophages using a transwell assay and also analyzed patient cardiac biopsy and blood single cell data."],"repository":["ENA"],"additional_accession":[]},"is_claimable":false,"name":"Targeting chemokine crosstalk between T-cells and macrophages to treat immune checkpoint inhibito-mediated myocarditis","description":"Targeting chemokine crosstalk between T-cells and macrophages to treat immune checkpoint inhibito-mediated myocarditis","dates":{"last_updated":"2025-09-24","first_public":"2025-02-03"},"accession":"PRJNA1051857","cross_references":{"GEO":["GSE250056"],"taxon":["10090"],"PubMed":["39931812"]}}