Welcome! Here, we present our study of immunotherapy-related myocarditis.
Please read and cite our original research article:
- Blum SM, Zlotoff DA, Smith NP, Kernin IJ, Ramesh S, Zubiri L, et al. Immune Responses in Checkpoint Myocarditis Across Heart, Blood, and Tumor. bioRxiv. 2023. p. 2023.09.15.557794. doi:10.1101/2023.09.15.557794
BibTeX
@ARTICLE{Blum2023-dg,
title = "{Immune Responses in Checkpoint Myocarditis Across Heart, Blood,
and Tumor}",
author = "Blum, Steven M and Zlotoff, Daniel A and Smith, Neal P and Kernin,
Isabela J and Ramesh, Swetha and Zubiri, Leyre and Caplin, Joshua
and Tirard, Alice and Sen, Prith and Song, Yuhui and Barth, Jaimie
L and Slowikowski, Kamil and Nasrallah, Mazen and Tantivit,
Jessica and Manakongtreecheep, Kasidet and Arnold, Benjamin Y and
McGuire, John and Pinto, Christopher J and McLoughlin, Daniel and
Jackson, Monica and Chan, Puiyee and Lawless, Aleigha and Sharova,
Tatyana and Nieman, Linda T and Gainor, Justin F and Juric, Dejan
and Mino-Kenudsen, Mari and Sullivan, Ryan J and Boland, Genevieve
M and Stone, James R and Thomas, Molly F and Neilan, Tomas G and
Reynolds, Kerry L and Villani, Alexandra-Chloe",
journal = "bioRxiv",
pages = "2023.09.15.557794",
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. \#\#\# Competing Interest Statement S.M.B has been a
paid consultant to Two River Consulting and Third Rock Ventures.
He has equity positions in Kronos Bio, 76Bio, and Allogene
Therapeutics. D.A.Z. has been a paid consultant to Bristol Myers
Squibb, Freeline Therapeutics, and Intrinsic Imaging. L.Z. has
received consulting fees from Bristol Myers Squibb and Merck.
R.J.S has been a paid consultant to Bristol Myers Squibb, Merck,
Pfizer, Marengo Therapeutics, Novartis, Eisai, Iovance, OncoSec,
and AstraZeneca and has received research funding from Merck.
T.G.N has been a paid consultant to Bristol Myers Squibb,
Genentech, CRC Oncology, Roche, Sanofi and Parexel Imaging
Pharmaceuticals and has received grant funding from Astra Zeneca
and Bristol Myers Squibb related to the cardiac effects of immune
checkpoint inhibitors. K.L.R has served as an advisory board to
SAGA Diagnostics and received speakers fees from CMEOutfitters and
Medscape as well as research funding from Bristol Myers Squibb.
A.C.V. has been a paid consultant to Bristol Myers Squibb.",
month = sep,
year = 2023,
doi = "10.1101/2023.09.15.557794",
language = "en"
}
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Cell Clusters
Metadata variables and gene expression in two-dimensional embeddings. Heart tissue cells:
Blood immune cells:
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This repository includes two main folders:
- Functions used in the analysis scripts.
- The scripts for our analyses.
The raw and processed scRNA-seq gene expression files are available at NCBI GEO GSE228597.
Sequencing reads will be available at dbGAP accession PLACEHOLDER.