Fibroblast growth factor receptor 3 alterations and response to immune checkpoint inhibition in metastatic urothelial cancer: a real world experience
Fibroblast growth factor receptor 3 alterations and response to immune checkpoint inhibition in metastatic urothelial cancer: a real world experience
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DOI：
10.1038/s41416-021-01488-6
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发表时间：
2021-07-22
影响因子：
8.8
通讯作者：
Kim, William Y.
中科院分区：
文献类型：
--
作者：
Rose, Tracy L.;Weir, William H.;Kim, William Y.
背景FGFR3改变的尿路上皮癌（UC）与非T细胞炎症表型相关，因此被认为对免疫检查点阻断（ICB）的反应较低。临床前工作表明，FGFR3信号传导可能会抑制干扰素信号传导等改变免疫微环境组成的途径。然而，检查临床试验的相关研究对于转移性UC患者中FGFR改变的肿瘤是否具有与ICB等效的反应和生存期一直存在冲突。这些发现尚未在真实的世界数据中得到验证，因此我们评价了ICB治疗FGFR 3改变的转移性UC患者的临床结局，并研究了应答和耐药的潜在免疫基因组学机制。方法确定了2014年至2018年在单一学术医疗中心接受ICB治疗的103例转移性UC患者。进行人口统计学和癌症结局的临床注释，以及体细胞DNA和RNA测序。比较有FGFR3基因改变和无FGFR3基因改变的患者对ICB的客观缓解率、无进展生存期和总生存期。RNA表达，包括分子亚型和T细胞受体克隆性，也比较了FGFR3改变和非改变患者之间。结果我们从该数据集的发现证实，FGFR3改变的（n = 17）和野生型（n = 86）膀胱癌对ICB的反应相同（12 vs 19%，p = 0.73）。此外，我们证明，尽管炎症较少，但FGFR3改变的肿瘤具有等同的T细胞受体（TCR）多样性，并且CD8 T细胞基因表达特征与免疫抑制特征的平衡是ICB反应的重要决定因素。结论我们在真实的世界数据集中的工作验证了先前临床试验的观察结果，但也扩展了先前的工作，以证明FGFR 3改变的肿瘤和野生型肿瘤具有相同的TCR多样性，并且效应T细胞与免疫抑制信号的平衡是ICB应答的重要决定因素。
Background FGFR3-altered urothelial cancer (UC) correlates with a non-T cell-inflamed phenotype and has therefore been postulated to be less responsive to immune checkpoint blockade (ICB). Preclinical work suggests FGFR3 signalling may suppress pathways such as interferon signalling that alter immune microenvironment composition. However, correlative studies examining clinical trials have been conflicting as to whether FGFR altered tumours have equivalent response and survival to ICB in patients with metastatic UC. These findings have yet to be validated in real world data, therefore we evaluated clinical outcomes of patients with FGFR3-altered metastatic UC treated with ICB and investigate the underlying immunogenomic mechanisms of response and resistance. Methods 103 patients with metastatic UC treated with ICB at a single academic medical center from 2014 to 2018 were identified. Clinical annotation for demographics and cancer outcomes, as well as somatic DNA and RNA sequencing, were performed. Objective response rate to ICB, progression-free survival, and overall survival was compared between patients with FGFR3-alterations and those without. RNA expression, including molecular subtyping and T cell receptor clonality, was also compared between FGFR3-altered and non-altered patients. Results Our findings from this dataset confirm that FGFR3-altered (n = 17) and wild type (n = 86) bladder cancers are equally responsive to ICB (12 vs 19%, p = 0.73). Moreover, we demonstrate that despite being less inflamed, FGFR3-altered tumours have equivalent T cell receptor (TCR) diversity and that the balance of a CD8 T cell gene expression signature to immune suppressive features is an important determinant of ICB response. Conclusions Our work in a real world dataset validates prior observations from clinical trials but also extends this prior work to demonstrate that FGFR3-altered and wild type tumours have equivalent TCR diversity and that the balance of effector T cell to immune suppression signals are an important determinant of ICB response.