与重叠性免疫相关心肌炎和肌炎不良临床结果相关的分子途径和细胞亚群。

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Bilal A Siddiqui, Nicolas L Palaskas, Sreyashi Basu, Yibo Dai, Zhong He, Shalini S Yadav, James P Allison, Rahul A Sheth, Sudhakar Tummala, Maximilian Buja, Meenakshi B Bhattacharjee, Cezar Iliescu, Anishia Rawther-Karedath, Anita Deswal, Linghua Wang, Padmanee Sharma, Sumit K Subudhi
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引用次数: 0

摘要

免疫检查点疗法(ICTs)可诱发危及生命的免疫相关不良事件,包括心肌炎和肌炎。人们对这些毒性的分子途径和免疫亚群仍然知之甚少。为了满足这一需求,我们在临床表现后96小时内,对接受过ICTs治疗的癌症患者进行了心脏和骨骼肌活检,并对入院时患有心肌炎和/或肌炎(重叠性心肌炎加肌炎,n=10;单纯性心肌炎,n=1)的患者进行了单细胞RNA测序,并与被排除毒性的ICT暴露患者作为对照(n=9)进行了比较。对58,523个细胞的分析表明,心肌炎和肌炎患者的CD8+T细胞都具有表达激活/衰竭标记的细胞毒性表型。此外,分析还发现了一群表达组织驻留标志和FcγRIIIa(CD16a)的髓样细胞,众所周知,FcγRIIIa能结合IgG并调节补体激活。受影响的心肌和骨骼肌组织的免疫组化显示了泛IgG和补体产物C4d的蛋白表达,这与部分患者血清中存在针对肌肉抗原的高滴度自身抗体有关。我们进一步确定了心肌炎中特异性富集的炎性 IL-1B+TNF+ 髓系细胞群,它们与更严重的毒性和更差的临床预后有关。这些结果首次在人类免疫相关心肌炎和肌炎组织中发现了这些髓系细胞亚群,并为研究克服这些高死亡率毒性的合理治疗方法提出了新的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Molecular Pathways and Cellular Subsets Associated with Adverse Clinical Outcomes in Overlapping Immune-Related Myocarditis and Myositis.

Immune checkpoint therapies (ICT) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we performed single-cell RNA sequencing of heart and skeletal muscle biopsies obtained from living patients with cancers treated with ICTs and admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n = 10; myocarditis-only, n = 1) or ICT-exposed patients ruled out for toxicity utilized as controls (n = 9). All biopsies were obtained within 96 hours of clinical presentation. Analyses of 58,523 cells revealed CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of myeloid cells expressing tissue-resident signatures and FcγRIIIa (CD16a), which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d, which were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results provide insight into the myeloid subsets present in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities. See related Spotlight by Fankhauser et al., p. 954.

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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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