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.

中文翻译：

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成纤维细胞生长因子受体 3 的改变和对转移性尿路上皮癌免疫检查点抑制的反应：真实世界的经验

背景

FGFR3 改变的尿路上皮癌 (UC) 与非 T 细胞炎症表型相关，因此被假定对免疫检查点阻断 (ICB) 的反应较低。临床前研究表明，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，关于 FGFR 改变的肿瘤是否对转移性 UC 患者的 ICB 具有相同的反应和存活率，检验临床试验的相关研究一直存在矛盾。这些发现尚未在现实​​世界数据中得到验证，因此我们评估了用 ICB 治疗的 FGFR3 改变的转移性 UC 患者的临床结果，并研究了反应和耐药的潜在免疫基因组机制。

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 名转移性 UC 患者。进行了人口统计学和癌症结果的临床注释，以及体细胞 DNA 和 RNA 测序。比较了有 FGFR3 改变的患者和没有改变的患者对 ICB 的客观反应率、无进展生存期和总生存期。还比较了 FGFR3 改变和未改变的患者之间的 RNA 表达，包括分子亚型和 T 细胞受体克隆性。

结果

我们对该数据集的研究结果证实，FGFR3 改变（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 改变的肿瘤具有相当的 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

我们在现实世界数据集中的工作验证了临床试验的先前观察结果，但也扩展了这项先前的工作，以证明 FGFR3 改变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一个重要的决定因素ICB 回应。