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Immune Responses in Checkpoint Myocarditis Across Heart, Blood, and Tumor.
Blum, Steven M; Zlotoff, Daniel A; Smith, Neal P; Kernin, Isabela J; Ramesh, Swetha; Zubiri, Leyre; Caplin, Joshua; Samanta, Nandini; Martin, Sidney C; Tirard, Alice; Sen, Pritha; Song, Yuhui; Barth, Jaimie; Slowikowski, Kamil; Nasrallah, Mazen; Tantivit, Jessica; Manakongtreecheep, Kasidet; Arnold, Benjamin Y; McGuire, John; Pinto, Christopher J; McLoughlin, Daniel; Jackson, Monica; Chan, PuiYee; Lawless, Aleigha; Sharova, Tatyana; Nieman, Linda T; Gainor, Justin F; Juric, Dejan; Mino-Kenudsen, Mari; Sullivan, Ryan J; Boland, Genevieve M; Stone, James R; Thomas, Molly F; Neilan, Tomas G; Reynolds, Kerry L; Villani, Alexandra-Chloé.
Affiliation
  • Blum SM; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Zlotoff DA; Massachusetts General Hospital, Cancer Center, Boston, MA, USA.
  • Smith NP; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Kernin IJ; Harvard Medical School, Boston, MA, USA.
  • Ramesh S; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Zubiri L; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Caplin J; Harvard Medical School, Boston, MA, USA.
  • Samanta N; Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Martin SC; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Tirard A; Massachusetts General Hospital, Cancer Center, Boston, MA, USA.
  • Sen P; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Song Y; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Barth J; Massachusetts General Hospital, Cancer Center, Boston, MA, USA.
  • Slowikowski K; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Nasrallah M; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Tantivit J; Massachusetts General Hospital, Cancer Center, Boston, MA, USA.
  • Manakongtreecheep K; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Arnold BY; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • McGuire J; Massachusetts General Hospital, Cancer Center, Boston, MA, USA.
  • Pinto CJ; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • McLoughlin D; Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • Jackson M; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Chan P; Massachusetts General Hospital, Cancer Center, Boston, MA, USA.
  • Lawless A; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Sharova T; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Nieman LT; Massachusetts General Hospital, Cancer Center, Boston, MA, USA.
  • Gainor JF; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Juric D; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Mino-Kenudsen M; Massachusetts General Hospital, Cancer Center, Boston, MA, USA.
  • Sullivan RJ; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Boland GM; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Stone JR; Massachusetts General Hospital, Cancer Center, Boston, MA, USA.
  • Thomas MF; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • Neilan TG; Harvard Medical School, Boston, MA, USA.
  • Reynolds KL; Transplant and Immunocompromised Host Program, Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital.
  • Villani AC; Massachusetts General Hospital, Cancer Center, Boston, MA, USA.
bioRxiv ; 2023 Nov 29.
Article in En | MEDLINE | ID: mdl-37790460
ABSTRACT
Immune checkpoint inhibitors (ICIs) are widely used anti-cancer therapies that can cause morbid and potentially fatal immune-related adverse events (irAEs). ICI-related myocarditis (irMyocarditis) is uncommon but has the highest mortality of any irAE. The pathogenesis of irMyocarditis and its relationship to anti-tumor immunity remain poorly understood. We sought to define immune responses in heart, tumor, and blood during irMyocarditis and identify biomarkers of clinical severity 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 heart and blood specimens identified cytotoxic T cells, inflammatory macrophages, conventional dendritic cells (cDCs), and fibroblasts enriched in irMyocarditis heart tissue. Additionally, potentially targetable, pro-inflammatory transcriptional programs were upregulated across multiple cell types. TCR clones enriched in heart and paired tumor tissue were largely non-overlapping, suggesting distinct T cell responses within these tissues. We also identify the presence of cardiac-expanded TCRs in a circulating, cycling CD8 T cell population as a novel peripheral biomarker of fatality. Collectively, these findings highlight critical biology driving irMyocarditis and putative biomarkers for therapeutic intervention.
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Full text: 1 Collection: 01-internacional Health context: 6_ODS3_enfermedades_notrasmisibles Database: MEDLINE Type of study: Prognostic_studies Language: En Journal: BioRxiv Year: 2023 Document type: Article
Fulltext
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PubMed Links
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Full text: 1 Collection: 01-internacional Health context: 6_ODS3_enfermedades_notrasmisibles Database: MEDLINE Type of study: Prognostic_studies Language: En Journal: BioRxiv Year: 2023 Document type: Article