Clonal CD8 T cells orchestrate arrhythmogenic inflammation in immune checkpoint inhibitor-associated myocarditis
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PROVIDER: PRJNA1272348 | ENA |
REPOSITORIES: ENA
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Project description:Clonal CD8 T cells orchestrate arrhythmogenic inflammation in immune checkpoint inhibitor-associated myocarditis
| PRJNA1271955 | ENA
Project description:Objective: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are frequently associated with immune-related adverse events, particularly in combination regimens. ICI-associated myocarditis (ICI-M) is rare but highly lethal, with a mortality rate approaching 50% and a notable risk of fatal ventricular arrhythmias. Prevention and effective management of ICI-M remain significant clinical challenges. This study aims to elucidate the immune landscape and spatial organization of immune cells in ICI-M using single-cell multi-omics in a preclinical mouse model. Methods: We utilized Ctla4+/–Pdcd1–/– mice, modeling human ICI-induced myocarditis. Single-cell RNA (scRNAseq) and T cell receptor (TCR) sequencing were performed on heart-infiltrating immune cells and peripheral blood mononuclear cells (PBMCs). Spatial transcriptomics was applied to map immune infiltration in cardiac tissue. Results: Approximately half of Ctla4+/–Pdcd1–/– mice died after 100 days, while Ctla4+/+ mice showed normal survival. ECG monitoring identified ventricular arrhythmias in 15% of Ctla4+/–Pdcd1–/– mice. Histology revealed severe myocardial inflammation and fibrosis. Cardiac scRNAseq data indicated that T cells were the predominant immune population in ICI-M hearts. TCR sequencing demonstrated substantial overlap in TCR clonotypes between cardiac-infiltrating and circulating CD8+ T cells. These TCR-shared CD8+ T cells exhibited an activated phenotype and were enriched in pathways associated with allograft rejection and inflammation. Spatial mapping revealed localization near the AV node and subendocardium, implicating potential CD8+ T cell–mediated conduction disruption. Conclusion: Clonal, activated CD8+ T cells contribute to arrhythmogenic myocarditis in ICI-M. Targeting specific TCR-peptide-MHC interactions may enable myocarditis prevention without impairing antitumor efficacy.
2025-06-11 | GSE299032 | GEO
Project description:Objective: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are frequently associated with immune-related adverse events, particularly in combination regimens. ICI-associated myocarditis (ICI-M) is rare but highly lethal, with a mortality rate approaching 50% and a notable risk of fatal ventricular arrhythmias. Prevention and effective management of ICI-M remain significant clinical challenges. This study aims to elucidate the immune landscape and spatial organization of immune cells in ICI-M using single-cell multi-omics in a preclinical mouse model. Methods: We utilized Ctla4+/–Pdcd1–/– mice, modeling human ICI-induced myocarditis. Single-cell RNA (scRNAseq) and T cell receptor (TCR) sequencing were performed on heart-infiltrating immune cells and peripheral blood mononuclear cells (PBMCs). Spatial transcriptomics was applied to map immune infiltration in cardiac tissue. Results: Approximately half of Ctla4+/–Pdcd1–/– mice died after 100 days, while Ctla4+/+ mice showed normal survival. ECG monitoring identified ventricular arrhythmias in 15% of Ctla4+/–Pdcd1–/– mice. Histology revealed severe myocardial inflammation and fibrosis. Cardiac scRNAseq data indicated that T cells were the predominant immune population in ICI-M hearts. TCR sequencing demonstrated substantial overlap in TCR clonotypes between cardiac-infiltrating and circulating CD8+ T cells. These TCR-shared CD8+ T cells exhibited an activated phenotype and were enriched in pathways associated with allograft rejection and inflammation. Spatial mapping revealed localization near the AV node and subendocardium, implicating potential CD8+ T cell–mediated conduction disruption. Conclusion: Clonal, activated CD8+ T cells contribute to arrhythmogenic myocarditis in ICI-M. Targeting specific TCR-peptide-MHC interactions may enable myocarditis prevention without impairing antitumor efficacy.
2025-06-11 | GSE298932 | GEO
Project description:Immune checkpoint inhibitors (ICIs) are improving cancer treatments strikingly. The raising use leads to the augmented occurrence of immune related events. Myocarditis is a rare, but severe form of these adverse events. Nine patients with proven ICI induced myocarditis were subjected to myocardial biopsy. The tissue was used for RNA-seq analyses.
2020-11-01 | E-MTAB-8867 | biostudies-arrayexpress
Project description:Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used widely to activate the immune system against tumor cells. Despite their therapeutic benefits, ICIs are known to cause immune-related adverse events (irAE) such as myocarditis, a rare but serious side effect with up to 50% mortality. To identify pathogenic immune subset(s) responsible for ICI myocarditis and other irAE, we performed single cell mass cytometry (CyTOF) on peripheral blood mononuclear cells from 40 patients and controls with irAE including four patients with ICI myocarditis. We also profiled 15 patients/controls using single cell RNA sequencing (scRNA-seq) with feature barcoding for surface marker expression confirmation. In both CyTOF/scRNAseq analyses, we found expansions of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in ICI myocarditis patients compared to controls. Using T cell receptor sequencing, we demonstrated a significant clonal expansion of CD8+ Temra cells in myocarditis patients. Transcriptomic profiling of these Temra CD8+ clones confirmed their highly activated and cytotoxic phenotype with expression of granzyme/perforin. Longitudinal data revealed the progression of these Temra CD8+ cells into an exhausted phenotype two months after diagnosis of myocarditis and after treatment with glucocorticoids. Differential expression of several proinflammatory chemokines (CCL4/CCL4L2/CCL5) was uncovered in the clonally expanded Temra CD8+ cells and ligand-receptor analysis implicated their regulation of other inflammatory cells such as monocytes and NK cells. These data suggest that the therapeutic modulation of these chemokines may serve as an attractive strategy for reducing life-threatening irAE in ICI-treated cancer patients.
2022-06-29 | GSE180045 | GEO
Project description:Immune checkpoint inhibitor-related myocarditis is the deadliest complication of immunotherapy. However, the underlying pathophysiological mechanisms of its occurrence and development remain unclear. Due to the long-term lack of effective early diagnosis and treatment options, it is of great significance to understand the pathophysiological mechanism of immune checkpoint inhibitor-related myocarditis.
2023-02-02 | PXD039793 |
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.
2023-07-01 | GSE227437 | GEO
Project description:Viral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a leading cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases, and pathological host immune responses. However, little is known regarding how viral infection can acutely induce an arrhythmogenic substrate prior to significant immune responses. Adenovirus is a leading cause of myocarditis, but due to species-specificity, models of infection are lacking and it is not understood how adenoviral infection may underlie sudden cardiac arrest. Mouse Adenovirus Type-3 (MAdV-3) was previously reported as cardiotropic, yet has not been utilized to understand mechanisms of cardiac infection and pathology. We have developed MAdV-3 infection as a model to investigate acute cardiac infection and molecular alterations to the infected heart prior to an appreciable immune response or gross cardiomyopathy. By optical mapping of infected hearts we find decreases in conduction velocity concomitant with increased Cx43Ser368 phosphorylation, a residue known to regulate gap junction function. Hearts from animals harboring a phospho-null mutation at Cx43Ser368 are protected against MAdV-3 induced conduction velocity slowing. Additional to gap junction alterations, patch clamping of MAdV-3-infected adult mouse ventricular cardiomyocytes reveals prolonged action potential duration as a result of decreased IK1 and IKs current density. Turning to human systems, we find human adenovirus type-5 (HAdV-5) increases phosphorylation of Cx43Ser368 and disrupts synchrony in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), indicating common mechanisms with our mouse whole heart and adult cardiomyocyte data. Together, these findings demonstrate that adenoviral infection creates an arrhythmogenic substrate through direct targeting of gap junction and ion channel function in the heart. Such alterations are known to precipitate arrhythmias and likely contribute to sudden cardiac death in acutely infected patients.
2024-03-29 | GSE246572 | GEO
Project description:Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment, but are particularly associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-PD-1 (programmed cell death 1) and anti-CTLA-4 (Cytotoxic T-lymphocyte Antigen-4) antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI-myocarditis as well as emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI-myocarditis all exhibited downregulation of MANF (Mesencephalic Astrocyte Derived Neurotrophic Factor) and HSPA5 (Heat Shock 70kDa Protein 5) in the heart; this downregulation was particularly striking in female mice. ICI-myocarditis was amplified by heart-specific genetic deletion of mouse Manf and was attenuated by administration of recombinant MANF protein, suggesting a causal role. Ironically, both MANF and HSPA5 were transcriptionally induced by liganded estrogen receptor-βbeta and inhibited by androgen receptor. However, ICI treatment reduced serum estradiol concentration to a greater extent in female compared to male mice. Treatment with an estrogen receptor β-specific agonist as well as androgen depletion therapy attenuated ICI-associated cardiac effects. Taken together, our data suggest that ICI treatment inhibits the estradiol-dependent expression of MANF/HSPA5 in the heart, curtailing the cardiomyocyte response to immune injury. This endocrine-cardiac-immune pathway offers new insights into the mechanisms of sex differences in cardiac disease and may offer treatment strategies for ICI-myocarditis.
2022-09-18 | GSE213468 | GEO
Project description:Comparative cardiac transcriptomics of immune checkpoint inhibitor induced myocarditis
| PRJEB37155 | ENA