Cardiac Myosin-Specific Autoimmune T Cells Contribute to Immune Checkpoint Inhibitor-Associated Myocarditis

Won, Tae Joon; Kalinoski, Hannah M.; Wood, Megan K.; Hughes, David; Jaime, Camille M.; Talor, Monica V.; Lasrado, Ninaad; Reddy, Jay; Čiháková, Daniela

doi:10.2139/ssrn.4065075

Cited by 2 publications

(1 citation statement)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…20 However, the recent discovery of a new form of fulminant myocarditis induced by immune checkpoint inhibitors has provided new insights into the pathophysiology of heart-directed immune responses. 9,21 In particular, the recent discovery that Pdcd1 -/-Ctla4 +/mice on the C57BL/6 genetic background develop lethal CD8 + T cell-dependent myocarditis has reignited the interest in cardiac epitope mapping on this genetic background. 17,22 The C57BL/6 mouse strain is the most common animal model used in cardiovascular and cardio-immunology basic research, with numerous transgenic substrains available for in vivo mechanistic studies.…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel myosin antigen activating CD8⁺T cells in C57BL/6 mice

Richter,

Bauer,

Bernsen

et al. 2024

Preprint

View full text Add to dashboard Cite

Heart-specific T cells play important roles in myocardial diseases, including myocarditis, myocardial infarction, and heart failure. However, only few cardiac antigens and their respective specific T cell receptors (TCRs) have been validated so far. Therefore, we sought to identify new cardiac T cell epitopes in C57BL/6 mice and to characterize the specific TCRs. Antigen mapping of myosin heavy chain alpha (MYHCA) led to the identification of a 9-mer epitope (MYHCA724-732) recognized by CD8+ T cells. Single-cell TCR sequencing (scTCR-seq) analysis of MYHCA-stimulated CD8+ T cells enabled the identification of distinct TCRs enriched on specific T cells. Selected TCRs inferred from scTCR-seq data were then expressed on reporter cell lines and functionally validated. Our study expands the toolkit required to study heart-directed immune responses by revealing a new cardiac antigen and specific TCRs. These tools will enable in vivo characterization of myosin-specific CD8+ T cells in murine models of myocardial diseases.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification of a novel myosin antigen activating CD8⁺T cells in C57BL/6 mice

Richter,

Bauer,

Bernsen

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

A Novel Therapeutic Approach using CXCR3 Blockade to Treat Immune Checkpoint Inhibitor-mediated Myocarditis

Huang,

Lee,

Sun

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: Immune checkpoint inhibitors (ICIs) are successful in treating many cancers but may cause immune-related adverse events. ICI-mediated myocarditis has a high fatality rate of up to 40%, with severe cardiovascular consequences. Targeted therapies for ICI myocarditis are currently lacking. Methods: We used a genetic mouse model of PD-1 deletion (MRL/Pdcd1-/-) along with a novel drug-treated ICI myocarditis mouse model to recapitulate the disease phenotype. We performed single-cell RNA-sequencing (scRNAseq), single-cell T-cell receptor sequencing (scTCRseq), and cellular indexing of transcriptomes and epitopes (CITE-seq) on immune cells isolated from MRL and MRL/Pdcd1-/- mice at serial timepoints. We assessed the impact of macrophage deletion in MRL/Pdcd1-/- mice, then inhibited CXC chemokine receptor 3 (CXCR3) in ICI-treated mice to assess therapeutic effect on myocarditis phenotype. Furthermore, we delineated functional effects of CXCR3 blockade on T-cell and macrophage interactions in a transwell assay. We then correlated the results in human single-cell multi-omics data from blood and heart biopsy data from patients with ICI myocarditis. Results: Single-cell multi-omics demonstrated expansion of CXCL9/10+CCR2+ macrophages and CXCR3hi CD8+ effector T-lymphocytes in the hearts of MRL/Pdcd1-/- mice correlating with onset of myocarditis development. Both depletion of CXCL9/10+CCR2+ macrophages and CXCR3 blockade respectively led to decreased CXCR3hiCD8+ T-cell infiltration into the heart and significantly improved survival. A transwell assay showed that selective blockade of CXCR3 and its ligand, CXCL10 decreased CD8+ T-cell migration towards macrophages, implicating this interaction in T-cell cardiotropism towards cardiac macrophages. Cardiac biopsies from patients with confirmed ICI myocarditis demonstrated infiltrating CXCR3+ lymphocytes and CXCL9+/CXCL10+ macrophages. Both mouse cardiac immune cells and patient peripheral blood immune cells revealed expanded TCRs correlating with CXCR3hi CD8+ T-cells in ICI myocarditis samples. Conclusions: These findings bring forth the CXCR3-CXCL9/10 axis as an attractive therapeutic target for ICI myocarditis treatment, and more broadly, as a druggable pathway in cardiac inflammation.

show abstract

Cardiac Myosin-Specific Autoimmune T Cells Contribute to Immune Checkpoint Inhibitor-Associated Myocarditis

Cited by 2 publications

References 45 publications

Identification of a novel myosin antigen activating CD8⁺T cells in C57BL/6 mice

Identification of a novel myosin antigen activating CD8⁺T cells in C57BL/6 mice

A Novel Therapeutic Approach using CXCR3 Blockade to Treat Immune Checkpoint Inhibitor-mediated Myocarditis

Contact Info

Product

Resources

About

Cardiac Myosin-Specific Autoimmune T Cells Contribute to Immune Checkpoint Inhibitor-Associated Myocarditis

Cited by 2 publications

References 45 publications

Identification of a novel myosin antigen activating CD8+T cells in C57BL/6 mice

Identification of a novel myosin antigen activating CD8+T cells in C57BL/6 mice

A Novel Therapeutic Approach using CXCR3 Blockade to Treat Immune Checkpoint Inhibitor-mediated Myocarditis

Contact Info

Product

Resources

About

Identification of a novel myosin antigen activating CD8⁺T cells in C57BL/6 mice

Identification of a novel myosin antigen activating CD8⁺T cells in C57BL/6 mice