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
Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Massachusetts General Hospital, Cancer Center, Boston, MA, USA.
bioRxiv. 2023 Nov 29:2023.09.15.557794. doi: 10.1101/2023.09.15.557794.
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.
免疫检查点抑制剂（ICIs）是广泛应用的抗癌疗法，可引发严重且可能致命的免疫相关不良事件（irAEs）。ICI相关心肌炎（irMyocarditis）并不常见，但在所有irAE中死亡率最高。irMyocarditis的发病机制及其与抗肿瘤免疫的关系仍知之甚少。我们试图通过对28例irMyocarditis患者和23例对照进行单细胞（sc）RNA测序并结合T细胞受体（TCR）测序、显微镜检查和蛋白质组学分析，来确定irMyocarditis期间心脏、肿瘤和血液中的免疫反应，并识别临床严重程度的生物标志物。我们对来自心脏和血液样本的284,360个细胞进行分析，确定了细胞毒性T细胞、炎性巨噬细胞、常规树突状细胞（cDCs）和成纤维细胞在irMyocarditis心脏组织中富集。此外，多种细胞类型中潜在可靶向的促炎转录程序上调。在心脏和配对肿瘤组织中富集的TCR克隆在很大程度上不重叠，表明这些组织内存在不同的T细胞反应。我们还确定，在循环的、处于周期中的CD8 T细胞群体中存在心脏扩增的TCR，作为一种新的死亡外周生物标志物。总体而言，这些发现突出了驱动irMyocarditis的关键生物学机制以及用于治疗干预的假定生物标志物。
