A targetable type III immune response with increase of IL-17A expressing CD4+ T cells is associated with immunotherapy-induced toxicity in melanoma

Affiliations

• Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland. florentia.dimitriou@usz.ch.
• Faculty of Medicine, University of Zurich, Zurich, Switzerland. florentia.dimitriou@usz.ch.
• Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.
• Faculty of Medicine, University of Zurich, Zurich, Switzerland.
• Department of Oncology, Geneva University Hospital, Geneva, Switzerland.
• Department of Dermatology, Johannes Wesling Medical Center, Ruhr University Bochum Campus Minden, Minden, Germany.
• Department of Dermatology, Medical School Hannover, Hannover, Germany.
• Functional Genomics Center Zurich, University of Zurich/ETH Zurich, Zurich, Switzerland.
• Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
• Department of Cardiology, University Heart Center and Center for Experimental Cardiology (CTEC), University Hospital Zurich and University of Zurich, Zurich, Switzerland.
• Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
• Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia.
• Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
• Institute of Experimental Immunology, University of Zurich (UZH), Zurich, Switzerland.
• Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland. Reinhard.Dummer@usz.ch.
• Faculty of Medicine, University of Zurich, Zurich, Switzerland. Reinhard.Dummer@usz.ch.

PMID:  39210005  DOI: 10.1038/s43018-024-00810-4

Abstract

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.

免疫检查点抑制剂是治疗晚期黑色素瘤的标准疗法，但其使用受到免疫相关不良事件的限制。基线血清和不良事件发生时的蛋白质组学分析及多重细胞因子和趋化因子检测表明，T细胞活动异常，且I型和III型免疫标志物表达存在差异。这与流式细胞术检测外周血在不良事件发生时CD4+ T细胞中IL-17A表达比例增加的发现相一致。对免疫治疗引起的皮疹和结肠炎进行的多重免疫组化和空间转录组学分析也显示，CD4+ T细胞中IL-17A表达比例增加。两名患有轻度心肌炎、结肠炎和皮疹的患者接受了抗IL-17A治疗后，不良事件得以解决。这项研究强调了III型CD4+ T细胞在不良事件发展中的潜在作用，并为使用抗IL-17A治疗不良事件的临床试验提供了原理性证据。