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Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti–PD-1 Immune Checkpoint Inhibitor Cancer Therapy

ABSTRACT: Myocarditis has emerged as an immune-related adverse event of immune-checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. Our new NOD-cMHCI/II-/-.DQ8 mouse strain expresses human HLA-DQ8 in the absence of classical murine MHC class I and II. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, anti-PD-1 administration accelerates skeletal muscle myositis development. Using RNA sequencing analyses we performed a thorough characterization of cardiac and skeletal muscle infiltrating T-cells, identifying shared and unique characteristics of both populations.

ORGANISM(S): Mus musculus

PROVIDER: GSE248625 | GEO | 2024/02/02

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.

Project description:Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases whose pathogenetic mechanisms are still poorly understood. Invalidation of the inducible T cell co-stimulator (Icos) gene on the diabetes-prone NOD mouse background leads to spontaneous autoimmune myositis, providing a tool for studying the pathophysiological mechanisms involved in muscle inflammation. Myositis in Icos-/- NOD mice is characterized by progressive muscle weakness with immune cell infiltration and expression of IFN-associated genes, thus resembling human myositis. Proteomic and spatial transcriptomic analysis of Icos-/- NOD mice muscle brought to light a profound metabolic dysregulation in myofibers. Electron microscopy analysis, mitochondrial respiration assessment and histoenzymology stainings revealed dramatic structural abnormalities and severe dysfunction of muscle mitochondria in diseased Icos-/- NOD mice. Consequently, muscle from these mice exhibited elevated reactive oxygen species (ROS) production and an oxidative stress-transcriptomic signature. Blocking IFN in Icos-/- NOD mice diminished immune cell infiltration and ROS production. Transcriptomic analysis of muscle biopsies from IIMs patients revealed a negative correlation between IFN and mitochondrial gene expression levels, and treatment of human myoblasts with IFN reduced the expression of mitochondrial respiratory chain genes, suggesting a link between IFN production and mitochondrial dysfunction. Sustaining a relevant pathogenic role for oxidative stress in the disease, preventive and therapeutic ROS-buffer treatments also significantly alleviated myositis while preserving mitochondrial ultrastructure and restoring muscle mitochondrial respiration in mice. Notably, preventive ROS-buffer treatment also reduced muscle inflammation. Together, our results suggest that ROS, mitochondrial dysfunction and inflammation are interconnected in a self-maintenance loop, opening perspectives for ROS targeting drugs and/or mitochondria therapy in myositis.

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Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti–PD-1 Immune Checkpoint Inhibitor Cancer Therapy

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