由于与组织驻留记忆T细胞相关的免疫检查点抑制剂,骨关节炎增加了炎性关节炎的风险。

IF 10.3 1区 医学 Q1 IMMUNOLOGY
Matthieu Paiola, Daniel M Portnoy, Luke Yi Hao, Shoiab Bukhari, Robert J Winchester, Brian S Henick, Adam Mor, Yevgeniya Gartshteyn
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引用次数: 0

摘要

目的:免疫检查点抑制剂(ICIs)具有显著的晚期癌症治疗作用,但它们也可能导致免疫相关不良事件(irAEs),包括炎症性关节炎。了解irAE发病的危险因素和潜在机制对于优化患者管理至关重要。越来越多的证据表明,ici介导的组织驻留记忆T细胞(TRM)的激活可显著消除癌细胞,并与irae相关的结肠炎和皮炎有关。然而,目前尚不清楚为什么这些irae的发展仅限于一小部分患者。我们假设骨关节炎(OA)相关的组织损伤和慢性炎症导致关节TRM细胞的募集和分化,使个体易患ici诱导的关节炎。方法:采用综合方法,我们比较了irAE关节炎患者与irAE非关节炎患者和无irAE患者的OA患病率。此外,我们使用先进的免疫分型技术来表征OA和irae关节炎患者血液和滑液中的t细胞群。结果:我们的研究结果显示,患irae关节炎的患者患OA的比例明显高于对照组。此外,多变量分析确定OA、体重指数和吸烟是irae关节炎发展的独立危险因素。表达程序性细胞死亡蛋白-1 (PD-1)的TRM细胞是OA关节中主要的滑膜T细胞。这些细胞被ICIs直接靶向,导致炎症免疫反应和从OA到irae关节炎的转变。结论:本研究首次将OA确定为缺血性地炎的重要危险因素。它揭示了ICIs激活OA关节中pd -1阳性TRM细胞,导致组织炎症和irae关节炎的潜在机制。本研究可显著提高肿瘤患者接受体外循环治疗的管理和治疗水平。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Osteoarthritis increases the risk of inflammatory arthritis due to immune checkpoint inhibitors associated with tissue-resident memory T cells.

Objective: Immune checkpoint inhibitors (ICIs) have significantly advanced cancer treatment, but they can also lead to immune-related adverse events (irAEs), including inflammatory arthritis. Understanding the risk factors and underlying mechanisms of irAE pathogenesis is crucial for optimal patient management. Increasing evidence suggests that ICI-mediated activation of tissue-resident memory T cells (TRM) significantly eliminates cancer cells and is associated with irAE-related colitis and dermatitis. However, it remains unknown why the development of these irAEs is restricted to a subset of patients. We hypothesized that osteoarthritis (OA) associated tissue damage and chronic inflammation lead to the recruitment and differentiation of joint TRM cells, predisposing individuals to ICI-induced arthritis.

Methods: Using a comprehensive approach, we compared the prevalence of OA in patients with irAE-arthritis to those with irAE non-arthritis and those without irAEs. Additionally, we used advanced immunophenotyping techniques to characterize T-cell populations in the blood and synovial fluid of patients with OA and irAE-arthritis.

Results: Our findings revealed a significantly higher prevalence of OA in patients who developed irAE-arthritis than controls. Furthermore, the multivariable analysis identified OA, body mass index, and smoking as independent risk factors for the development of irAE-arthritis. TRM cells expressing programmed cell death protein-1 (PD-1) were the predominant synovial T cells in OA joints. These cells were directly targeted by ICIs, resulting in an inflammatory immune response and the transition from OA to irAE-arthritis.

Conclusion: This study, the first of its kind, identifies OA as a significant risk factor for irAEarthritis. It reveals a potential mechanism by which ICIs activate PD-1-positive TRM cells in OA joints, resulting in tissue inflammation and irAE-arthritis. This research could significantly enhance the management and treatment of patients with cancer receiving ICIs.

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来源期刊
Journal for Immunotherapy of Cancer
Journal for Immunotherapy of Cancer Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
17.70
自引率
4.60%
发文量
522
审稿时长
18 weeks
期刊介绍: The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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