表达 IL-17A 的 CD4+ T 细胞增多的可靶向 III 型免疫反应与免疫疗法诱导的黑色素瘤毒性有关。

IF 23.5 1区 医学 Q1 ONCOLOGY Nature cancer Pub Date : 2024-08-29 DOI:10.1038/s43018-024-00810-4
Florentia Dimitriou, Phil F. Cheng, Annalisa Saltari, Katrin Schaper-Gerhardt, Ramon Staeger, Veronika Haunerdinger, Federica Sella, Aizhan Tastanova, Christian Urban, Susanne Dettwiler, Daniela Mihic-Probst, Christian M. Matter, Olivier Michielin, Ralf Gutzmer, Georgina V. Long, Burkhard Becher, Mitchell P. Levesque, Reinhard Dummer
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引用次数: 0

摘要

免疫检查点抑制剂是治疗晚期黑色素瘤的标准药物,但其使用受到免疫相关不良事件的限制。对基线和不良事件发生时的血清进行蛋白质组分析以及多重细胞因子和趋化因子检测表明,T细胞活性异常,I型和III型免疫特征的表达存在差异。这与流式细胞术发现的不良事件发生时外周血中表达 IL-17A 的 CD4+ T 细胞比例增加的结果一致。免疫疗法诱发的皮疹和结肠炎的多重免疫组化和空间转录组学显示,表达 IL-17A 的 CD4+ T 细胞比例增加。两名患有轻度心肌炎、结肠炎和皮疹的患者接受了抗IL-17A治疗,不良反应得到缓解。这项研究强调了 III 型 CD4+ T 细胞在不良事件发生中的潜在作用,并为使用抗 IL-17A 治疗不良事件的临床试验提供了原则性证据。
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A targetable type III immune response with increase of IL-17A expressing CD4+ T cells is associated with immunotherapy-induced toxicity in melanoma
Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4+ T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4+ T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4+ T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events. Dimitriou et al. perform multiomic profiling of patients with melanoma experiencing immunotherapy-associated toxicity and identify a targetable role for type III-associated immune responses with an increase in CD4+ T cells expressing IL-17A.
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来源期刊
Nature cancer
Nature cancer Medicine-Oncology
CiteScore
31.10
自引率
1.80%
发文量
129
期刊介绍: Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.
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