{"doi":"10.1101/2023.04.28.538426","title":"Expansion of Disease Specific Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis","abstract":"Abstract Background Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1/PD-L1 or CTLA4 have revolutionized cancer management but are associated with devastating immune-related adverse events (irAEs) including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI-myocarditis is often fulminant and is pathologically characterized by myocardial infiltration of T lymphocytes and macrophages. While much has been learned regarding the role of T-cells in ICI-myocarditis, little is understood regarding the identity, transcriptional diversity, and functions of infiltrating macrophages. Methods We employed an established murine ICI myocarditis model ( Ctla4 +/- Pdcd1 -/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, flow cytometry, in situ RNA hybridization and molecular imaging and antibody neutralization studies. Results We observed marked increases in CCR2 + monocyte-derived macrophages and CD8 + T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2 + subpopulation highly expressing Cxcl9 , Cxcl10 , Gbp2b , and Fcgr4 that originated from CCR2 + monocytes. Importantly, a similar macrophage population expressing CXCL9 , CXCL10 , and CD16α (human homologue of mouse FcgR4) was found selectively expanded in patients with ICI myocarditis compared to other forms of heart failure and myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9 + Cxcl10 + macrophages via IFN-γ and CXCR3 signaling pathways. Depleting CD8 + T-cells, macrophages, and blockade of IFN-γ signaling blunted the expansion of Cxcl9 + Cxcl10 + macrophages in the heart and attenuated myocarditis suggesting that this interaction was necessary for disease pathogenesis. Conclusion These data demonstrate that ICI-myocarditis is associated with the expansion of a specific population of IFN-γ induced inflammatory macrophages and suggest the possibility that IFN-γ blockade may be considered as a treatment option for this devastating condition.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":393213,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9601,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1021270,"name":"Jing Liu","orcid":"0009-0007-4907-0228","position":1,"is_corresponding":false},{"id":840044,"name":"Juan Qin","orcid":"0000-0002-0821-6290","position":2,"is_corresponding":false},{"id":552524,"name":"Lulu Lai","orcid":"0000-0002-3352-9467","position":3,"is_corresponding":false},{"id":273847,"name":"Gyu Seong Heo","orcid":"0000-0001-6200-4742","position":4,"is_corresponding":false},{"id":273845,"name":"Hannah Luehmann","orcid":"0000-0002-7516-6772","position":5,"is_corresponding":false},{"id":354866,"name":"Deborah Sultan","orcid":null,"position":6,"is_corresponding":false},{"id":552521,"name":"Andrea Bredemeyer","orcid":"0000-0003-2970-5998","position":7,"is_corresponding":false},{"id":1017530,"name":"Geetika Bajapa","orcid":null,"position":8,"is_corresponding":false},{"id":622856,"name":"Guoshuai Feng","orcid":"0000-0003-3951-0975","position":9,"is_corresponding":false},{"id":933001,"name":"Jesús Jiménez","orcid":"0000-0001-5399-8538","position":10,"is_corresponding":false},{"id":868538,"name":"Antanisha Parks","orcid":"0000-0001-5985-6776","position":11,"is_corresponding":false},{"id":867739,"name":"Junedh Amrute","orcid":"0000-0002-6851-0168","position":12,"is_corresponding":false},{"id":1016730,"name":"Ana Villanueva","orcid":"0000-0002-6637-3745","position":13,"is_corresponding":false},{"id":273860,"name":"Yongjian Liu","orcid":"0000-0002-1118-1535","position":14,"is_corresponding":false},{"id":282754,"name":"Chieh‐Yu Lin","orcid":"0000-0002-4269-3234","position":15,"is_corresponding":false},{"id":471317,"name":"Matthias Mack","orcid":"0000-0002-3157-7262","position":16,"is_corresponding":false},{"id":840048,"name":"Kaushik Amancherla","orcid":"0000-0003-3379-5834","position":17,"is_corresponding":false},{"id":232185,"name":"Javid J. 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