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Decoding the immune checkpoint signatures in human atherosclerosis: implications of type 2 diabetes and lipid-lowering intervention [mouse_plaque_scRNAseq]

ABSTRACT: Immune checkpoint inhibitor (ICI) therapies in cancer accelerate atherosclerosis progression. Here, we have charted the landscape of immune checkpoint gene expression and defined the network of disease-relevant interactions with single-cell resolution. We found that signaling through PD-1 and CTLA4 is driven by a population of dendritic cells enriched for FSCN1 that can be derived from peripheral blood cells following anti-PD-1 or -CTLA4 treatment ex vivo. Type 2 diabetes dampened plaque PD-1 and CTLA4 signaling, showing that cardiometabolic comorbidities elicit unique responses to ICIs. Lipid-lowering therapy equalized the intensity and direction of immune checkpoint interactions in human blood, while atherosclerotic mice subjected to a lipid-lowering diet displayed both increased co-inhibitory signaling and a downregulation of inflammatory transcriptional programs in plaques. Our findings underscore the potential of lipid-lowering therapies in stabilizing immune checkpoint interactions and reducing plaque inflammation, offering new insights on atherosclerosis and cardiovascular risks in cancer patients undergoing ICI treatments.

ORGANISM(S): Mus musculus

PROVIDER: GSE246316 | GEO | 2024/10/07

REPOSITORIES: GEO

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Project description: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 pathophysiologically 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. We employed an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, and molecular imaging. 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 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) were found selectively 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 and blockade of IFN-γ signaling blunted the emergence of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis suggesting that this interaction was necessary for disease pathogenesis. Collectively, these data demonstrate that ICI-myocarditis is associated with the emergence of a specific population of inflammatory macrophages and suggest the possibility that IFN-γ blockade may serve as an effective treatment for this devastating condition.

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Decoding the immune checkpoint signatures in human atherosclerosis: implications of type 2 diabetes and lipid-lowering intervention [mouse_plaque_scRNAseq]

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