| First Author | Ma P | Year | 2024 |
| Journal | Circulation | Volume | 149 |
| Issue | 1 | Pages | 48-66 |
| PubMed ID | 37746718 | Mgi Jnum | J:357407 |
| Mgi Id | MGI:7714839 | Doi | 10.1161/CIRCULATIONAHA.122.062551 |
| Citation | Ma P, et al. (2024) Expansion of Pathogenic Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis. Circulation 149(1):48-66 |
| abstractText | BACKGROUND: Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1) or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), have revolutionized cancer management but are associated with devastating immune-related adverse events 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. Although much has been learned about the role of T-cells in ICI myocarditis, little is understood about the identity, transcriptional diversity, and functions of infiltrating macrophages. METHODS: We used 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, molecular imaging, and antibody neutralization studies. RESULTS: We observed marked increases in CCR2 (C-C chemokine receptor type 2)(+) 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 (chemokine [C-X-C motif] ligand 9), Cxcl10 (chemokine [C-X-C motif] ligand 10), Gbp2b (interferon-induced guanylate-binding protein 2b), and Fcgr4 (Fc receptor, IgG, low affinity IV) that originated from CCR2(+) monocytes. It is important that a similar macrophage population expressing CXCL9, CXCL10, and CD16alpha (human homologue of mouse FcgR4) was expanded in patients with ICI myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9(+)Cxcl10(+) macrophages via IFN-gamma (interferon gamma) and CXCR3 (CXC chemokine receptor 3) signaling pathways. Depleting CD8(+) T-cells or 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. CONCLUSIONS: 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. |
