| First Author | Ma P | Year | 2023 |
| Journal | bioRxiv | PubMed ID | 37162929 |
| Mgi Jnum | J:356834 | Mgi Id | MGI:7762926 |
| Doi | 10.1101/2023.04.28.538426 | Citation | Ma P, et al. (2023) Expansion of Disease Specific Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis. bioRxiv |
| abstractText | 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 CD16alpha (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-gamma and CXCR3 signaling pathways. Depleting CD8 (+) T-cells, macrophages, and blockade of IFN-gamma 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-gamma induced inflammatory macrophages and suggest the possibility that IFN-gamma blockade may be considered as a treatment option for this devastating condition. |
