尿路上皮对干扰素γ的转录组反应：对膀胱癌预后和免疫治疗的影响。
The Urothelial Transcriptomic Response to Interferon Gamma: Implications for Bladder Cancer Prognosis and Immunotherapy.
作者信息
Baker Simon C, Mason Andrew S, Slip Raphael G, Eriksson Pontus, Sjödahl Gottfrid, Trejdosiewicz Ludwik K, Southgate Jennifer
机构信息
Jack Birch Unit of Molecular Carcinogenesis, Department of Biology and York Biomedical Research Institute, University of York, Heslington, York YO10 5DD, UK.
Division of Oncology, Department of Clinical Sciences Lund, Lund University, 22184 Lund, Sweden.
出版信息
Cancers (Basel). 2022 Oct 27;14(21):5295. doi: 10.3390/cancers14215295.
Interferon gamma (IFNγ) is central to the inflammatory immune response, such as that entrained by BCG immunotherapy for bladder cancer. However, immune-mediated tumour cell killing is subject to modulation by immunoinhibitory "checkpoint" receptors such as PD-L1. We investigated the effects of IFNγ on barrier-forming in vitro-differentiated normal human urothelium using mRNA-sequencing, and showed canonical upregulation of MHC class I/II and de novo expression of the T cell tropic CXCL9-11 chemokines. Normal urothelium constitutively expressed immunoinhibitory B7 family member (VISTA), while (PD-L1) expression was induced/upregulated by IFNγ. We generated a urothelial IFNγ response gene signature. When applied to the unsupervised clustering of non-muscle-invasive bladder cancers, the IFNγ-signature predicted longer recurrence-free survival. In muscle-invasive cancers, the IFNγ-signature split the basal/squamous consensus subtype, with significantly worse overall survival when weak or absent. This study offers novel insights into strategies to enhance immunotherapy via the IFNγ and VISTA/PD-L1 nexus.
γ干扰素（IFNγ）在炎症免疫反应中起核心作用，例如卡介苗免疫疗法治疗膀胱癌所引发的免疫反应。然而，免疫介导的肿瘤细胞杀伤作用会受到免疫抑制性“检查点”受体（如PD-L1）的调节。我们使用mRNA测序研究了IFNγ对体外分化的正常人尿路上皮屏障形成的影响，并显示主要组织相容性复合体I/II类分子呈典型上调，且趋化因子CXCL9 - 11（对T细胞有趋化作用）出现从头表达。正常尿路上皮组成性表达免疫抑制性B7家族成员（VISTA），而（PD-L1）的表达则由IFNγ诱导/上调。我们生成了尿路上皮IFNγ反应基因特征。将其应用于非肌层浸润性膀胱癌的无监督聚类时，IFNγ特征预测无复发生存期更长。在肌层浸润性癌中，IFNγ特征将基底/鳞状共识亚型区分开来，当该特征较弱或不存在时，总生存期显著更差。本研究为通过IFNγ与VISTA/PD-L1关系增强免疫疗法的策略提供了新见解。
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