美国马萨诸塞州总医院Alexandra-Chloé Villani研究团队揭示跨越心脏、血液和肿瘤的检查点心肌炎免疫反应。2024年11月6日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员通过利用单细胞RNA测序结合T细胞受体（TCR）测序、显微镜和蛋白质组学分析，定义了28名免疫相关性心肌炎（irMyocarditis）患者和41名未受影响个体在心脏、肿瘤和血液中的免疫反应。

通过对84576个心脏细胞进行单细胞RNA测序和多重显微镜分析，研究人员发现irMyocarditis患者的心脏组织中，细胞毒性T细胞、常规树突状细胞和炎症成纤维细胞的频率增加，并且这些细胞共定位。对366066个血液细胞的分析显示，irMyocarditis患者的血液中，浆细胞样树突状细胞、常规树突状细胞和B细胞的频率降低，而其他单核吞噬细胞的频率增加。

来自8名患者的52个心脏扩展的TCR克隆，未能识别假定的心脏自体抗原α-肌球蛋白、肌钙蛋白I或肌钙蛋白T。此外，在心脏组织富集的TCR与肿瘤组织中富集的TCR基本没有重叠。心脏扩展的TCR在循环血液中的CD8 T细胞群体中的存在，与致命性irMyocarditis病例的状态相关。总的来说，这些发现突出了驱动irMyocarditis的关键生物学机制，并识别了潜在的生物标志物。

据介绍，免疫检查点抑制剂是广泛使用的抗癌疗法，但它们可能引发严重且可能致命的免疫相关不良事件，如irMyocarditis。irMyocarditis的发病机制及其与抗肿瘤免疫的关系仍然未被充分理解。

附：英文原文

Title: Immune responses in checkpoint myocarditis across heart, blood and tumour

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

Issue&Volume: 2024-11-06

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)2,3,4,5. 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 Tcell 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 Tcells, 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 Blineage 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, troponinI or troponinT. 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 Tcell population was associated with fatal irMyocarditis case status. Collectively, these findings highlight crucial biology driving irMyocarditis and identify putative biomarkers.

DOI: 10.1038/s41586-024-08105-5

Source: https://www.nature.com/articles/s41586-024-08105-5