Immunologic drivers of immune checkpoint inhibitor therapy myocarditis, fatality and anti-tumor response in cancer patients
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PROVIDER: PRJNA950416 | ENA |
REPOSITORIES: ENA
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Project description:Immune checkpoint inhibitors (ICIs) can offer remarkable benefits to patients with cancer, but these agents can cause morbid and potentially fatal immune-related adverse events (irAEs), the most lethal of which is ICI-related myocarditis (irMyocarditis). The pathogenesis of irMyocarditis and its relationship to anti-tumor immunity remain poorly understood. We sought to define how immune cell trafficking between heart, tumor and blood contributes to irMyocarditis pathogenesis and fatality by leveraging single-cell (sc)RNA-seq coupled with T cell receptor (TCR) sequencing, microscopy, and proteomics analysis of 28 irMyocarditis patients and 23 controls. Our analysis of ~284,360 cells from the heart and blood specimens identified enrichment of cytotoxic T-cell subsets, inflammatory macrophage subsets, conventional dendritic cells (cDCs), and fibroblasts in the heart that accompany the upregulation of potentially targetable, pro-inflammatory transcriptional programs. Expanded TCR clones enriched in irMyocarditis are largely distinct from those in paired tumors, suggesting distinct mechanisms between anti-tumor immune response and irMyocarditis. We also identified circulating biomarkers of fatality, including decreased circulating CD4+ T cells, decreased cDCs, and the presence of cardiac-expanded TCRs in a circulating, cycling CD8+ T cell population. Collectively, these findings highlight critical biology driving disease pathogenesis and nominate putative biomarkers and tailored therapeutic interventions for patients with irMyocarditis.
2024-06-22 | GSE228597 | 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), 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: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 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
Project description: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.
2024-02-02 | GSE248625 | 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:Emergence of Disease Specific Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis
| PRJNA945054 | ENA
Project description:Identification of Pathogenic Immune Cell Subsets in Checkpoint Inhibitor-induced Myocarditis
| PRJNA746332 | ENA