Immune responses in checkpoint myocarditis across heart, blood and tumour

Steven M. Blum, Daniel A. Zlotoff, Neal P. Smith, Isabela J. Kernin, Swetha Ramesh, Leyre Zubiri, Joshua Caplin, Nandini Samanta, Sidney Martin, Mike Wang, Alice Tirard, Yuhui Song, Katherine H. Xu, Jaimie Barth, Pritha Sen, Kamil Slowikowski, Jessica Tantivit, Kasidet Manakongtreecheep, Benjamin Y. Arnold, Mazen Nasrallah, Christopher J. Pinto, Daniel McLoughlin, Monica Jackson, PuiYee Chan, Aleigha Lawless, William A. Michaud, Tatyana Sharova, Linda T. Nieman, Justin F. Gainor, Catherine J. Wu, Dejan Juric, Mari Mino-Kenudson, Giacomo Oliveira, Ryan J. Sullivan, Genevieve M. Boland, James R. Stone, Molly F. Thomas, Tomas G. Neilan, Kerry L. Reynolds and Alexandra-Chloé Villani ()
Additional contact information
Steven M. Blum: Massachusetts General Hospital
Daniel A. Zlotoff: Massachusetts General Hospital
Neal P. Smith: Massachusetts General Hospital
Isabela J. Kernin: Massachusetts General Hospital
Swetha Ramesh: Massachusetts General Hospital
Leyre Zubiri: Massachusetts General Hospital
Joshua Caplin: Massachusetts General Hospital
Nandini Samanta: Massachusetts General Hospital
Sidney Martin: Massachusetts General Hospital
Mike Wang: Mass General Cancer Center
Alice Tirard: Massachusetts General Hospital
Yuhui Song: Massachusetts General Hospital
Katherine H. Xu: Massachusetts General Hospital
Jaimie Barth: Massachusetts General Hospital
Pritha Sen: Massachusetts General Hospital
Kamil Slowikowski: Massachusetts General Hospital
Jessica Tantivit: Massachusetts General Hospital
Kasidet Manakongtreecheep: Massachusetts General Hospital
Benjamin Y. Arnold: Massachusetts General Hospital
Mazen Nasrallah: Massachusetts General Hospital
Christopher J. Pinto: Mass General Cancer Center
Daniel McLoughlin: Mass General Cancer Center
Monica Jackson: Mass General Cancer Center
PuiYee Chan: Mass General Cancer Center
Aleigha Lawless: Massachusetts General Hospital
William A. Michaud: Massachusetts General Hospital
Tatyana Sharova: Massachusetts General Hospital
Linda T. Nieman: Harvard Medical School
Justin F. Gainor: Mass General Cancer Center
Catherine J. Wu: Broad Institute of Massachusetts Institute of Technology and Harvard
Dejan Juric: Mass General Cancer Center
Mari Mino-Kenudson: Harvard Medical School
Giacomo Oliveira: Broad Institute of Massachusetts Institute of Technology and Harvard
Ryan J. Sullivan: Mass General Cancer Center
Genevieve M. Boland: Broad Institute of Massachusetts Institute of Technology and Harvard
James R. Stone: Harvard Medical School
Molly F. Thomas: Massachusetts General Hospital
Tomas G. Neilan: Harvard Medical School
Kerry L. Reynolds: Mass General Cancer Center
Alexandra-Chloé Villani: Massachusetts General Hospital

Nature, 2024, vol. 636, issue 8041, 215-223

Abstract: Abstract Immune checkpoint inhibitors are widely used anticancer therapies1 that can cause morbid and potentially fatal immune-related adverse events such as immune-related myocarditis (irMyocarditis)2–5. The pathogenesis of irMyocarditis and its relationship to antitumour immunity remain poorly understood. Here we sought to define immune responses in heart, tumour and blood in patients with irMyocarditis by leveraging single-cell RNA sequencing coupled with T cell receptor (TCR) sequencing, microscopy and proteomics analyses of samples from 28 patients with irMyocarditis and 41 unaffected individuals. Analyses of 84,576 cardiac cells by single-cell RNA sequencing combined with multiplexed microscopy demonstrated increased frequencies and co-localization of cytotoxic T cells, conventional dendritic cells and inflammatory fibroblasts in irMyocarditis heart tissue. Analyses of 366,066 blood cells revealed decreased frequencies of plasmacytoid dendritic cells, conventional dendritic cells and B lineage cells but an increased frequency of other mononuclear phagocytes in irMyocarditis. Fifty-two heart-expanded TCR clones from eight patients did not recognize the putative cardiac autoantigens α-myosin, troponin I or troponin T. Additionally, TCRs enriched in heart tissue were largely nonoverlapping with those enriched in paired tumour tissue. The presence of heart-expanded TCRs in a cycling blood CD8 T cell population was associated with fatal irMyocarditis case status. Collectively, these findings highlight crucial biology driving irMyocarditis and identify putative biomarkers.

Date: 2024
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DOI: 10.1038/s41586-024-08105-5

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