PO.CL12.01 · 临床研究

不同的肿瘤微环境格局定义了非肌层浸润性膀胱癌的分子亚型

Distinct tumor microenvironmental landscapes define molecular subtypes in non-muscle-invasive bladder cancer

编号 3868 展板 1 时间 4/20 02:00–05:00 区域 Section 46 主讲 Frank DeRosa

分会场 Molecular Classification and Tumor Biology in Cancer

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作者与单位 Authors & Affiliations

Songjun Xu¹, Matthew H. V. Byrne², Jiarui Zhang¹, Ahmad Alalti², Devika Agarwal³, Neil Beeharry¹, Olesya Chornoguz¹, Kyla Dooley⁴, Kin Cheung Lee⁴, Shuwei Li¹, Guneet Walia¹, Tommaso Mansi¹, Joel Greshock¹, Calliope Dendrou⁵, Freddie Hamdy⁶, Lisa Browning⁷, Dan J. Woodcock², Patrick Wilkinson¹, Shibu Thomas¹

¹Johnson & Johnson, Spring House, PA,²Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom,³Kennedy Institute, University of Oxford, Oxford, United Kingdom,⁴Centre for Human Genetics, University of Oxford, Oxford, United Kingdom,⁵Kennedy Institute, University of Oxford; Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom,⁶Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom, Department of Urology, Oxford University Hospitals NHS Foundation Trust; NIHR Biomedical Research Centre, Oxford, United Kingdom,⁷Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom

摘要 Abstract

中文摘要

背景：非肌层浸润性膀胱癌（NMIBC）是生物学上异质性的肿瘤，仅根据分期/分级进行分类，而这并不能提供准确的区分，因为它忽略了潜在的分子表型。UROMOL分子分类源自对NMIBC的大规模转录组分析（Lindskrog SV等，Nat Commun. 2021;12:2301），将肿瘤分层为与预后相关、具有不同分子亚型的生物学类型。分子状态与肿瘤微环境（TME）组成之间的关系仍不明确。方法：我们对NMIBC肿瘤（患者n=16，样本n=34，细胞n=108108）进行了转录组亚型分型和单细胞水平的TME分析。使用NMIBC分类器（Lindskrog SV等，Nat Commun. 2021;12:2301），基于汇总的基因表达谱将肿瘤分类为UROMOL亚型。我们量化了上皮、基质和免疫群体，并使用精选的免疫和基质基因模块评分评估了通路活性。结果：观察到3种UROMOL亚型：Class 1（管腔乳头状型）、Class 2a（基底-炎症型）和Class 2b（管腔-炎症型）。Class 1肿瘤（n=6，17.6%）表现为上皮主导、免疫冷的TME，特征为约80.1%的上皮细胞（95% CI：74-86.2%）和极少的免疫浸润，包括T细胞（约1.9%，CI：0.5-3.3%）、巨噬细胞（约1.4%，CI：0.5-3.3%）和成纤维细胞（约8.4%，CI：4.3-12.5%）。这种组成与分化的管腔生物学一致，可能具有良好的基线预后。Class 2a肿瘤（n=9，26.5%）显示出不同的TME组成模式，与Class 1相比，T细胞（约4.8%，CI：1.7-8.0%）和巨噬细胞（约1.9%，CI：0.6-3.1%）浸润增加，同时成纤维细胞（约17.5%，CI：9.6-25.3%）和内皮细胞（约8.1%，CI：4.9-11.4%）含量增加。这些肿瘤显示出更高的效应和检查点活性，反映出比Class 1更活跃的免疫微环境。Class 2b肿瘤（n=19，55.9%）显示出异质性的免疫-基质格局，成纤维细胞显著富集（约27%，CI：19.7-34.4%）并伴细胞外基质重塑，同时免疫浸润升高，包括T细胞（约17.5%，CI：15-20.0%）和巨噬细胞（约11.2%，CI：7.4-14.9%），这反映了一种免疫活跃、成纤维细胞丰富的TME构架。结论： UROMOL亚型由不同的TME构架所定义，其细胞组成存在差异，从免疫冷、上皮丰富的Class 1肿瘤到高度免疫浸润、富含T细胞和成纤维细胞的Class 2b肿瘤。鉴于样本量有限，这些观察结果应在更大的队列中加以验证。本研究表明，NMIBC的UROMOL分子类别与不同的TME相关，揭示了免疫浸润和基质组成方面具有生物学意义的差异。

查看英文原文 English abstract

Background: Non-muscle-invasive bladder cancer (NMIBC) are biologically heterogeneous tumors that are classified based on stage/grade alone, which does not provide an accurate separation as it misses underlying molecular phenotypes. The UROMOL molecular classification, derived from large-scale transcriptomic profiling of NMIBC (Lindskrog SV, et al. Nat Commun . 2021;12:2301), stratifies tumors into prognosis-associated biology with distinct molecular subtypes. The relationship between molecular states and tumor microenvironment (TME) composition remains poorly defined. Methods: We performed transcriptomic subtyping and single-cell-level TME profiling of NMIBC tumors (patient n=16, sample n=34, cell n = 108108). Tumors were classified into UROMOL subtypes using NMIBC classifier (Lindskrog SV, et al. Nat Commun . 2021;12:2301) based on aggregated gene expression profiles. We quantified epithelial, stromal, and immune populations, and assessed pathway activity using curated immune and stromal gene module scores. Results: 3 UROMOL subtypes were observed: Class 1 (luminal papillary), Class 2a (basal-inflamed), and Class 2b (luminal-inflamed). Class 1 tumors (n=6, 17.6%) exhibited an epithelial-dominant, immune-cold TME characterized by ~80.1% epithelial cells (95% CI: 74-86.2%) and minimal immune infiltration, including T cells (~1.9%, CI: 0.5-3.3%), macrophages (~1.4%, CI: 0.5-3.3%), and fibroblasts (~8.4%, CI: 4.3-12.5%). This composition is consistent with differentiated luminal biology and may have favorable baseline prognosis. Class 2a tumors (n=9, 26.5%) displayed a distinct TME composition pattern, with an increase in T-cell (~4.8%, CI: 1.7-8.0%) and macrophage (~1.9%, CI: 0.6-3.1%) infiltration compared to Class 1, alongside increased fibroblast (~17.5%, CI: 9.6-25.3%) and endothelial (~8.1%, CI: 4.9-11.4%) content. These tumors showed increased effector and checkpoint activity, reflecting a more active immune microenvironment than class 1. Class 2b tumors (n=19, 55.9%) showed a heterogeneous immune-stromal landscape with pronounced fibroblast enrichment (~27%, CI: 19.7-34.4%) and extracellular matrix remodeling, alongside elevated immune infiltration, including T cells (~17.5%, CI: 15-20.0%) and macrophages (~11.2%, CI: 7.4-14.9%), this reflects an immune-active, fibroblast-rich TME architecture. Conclusions: UROMOL subtypes are defined by distinct TME architectures with differences in cellular composition from immune-cold, epithelial-rich Class 1 tumors to highly immune infiltrated Class 2b tumors enriched with T cells and fibroblasts. Given the limited sample size, these observations should be validated in a larger cohort. This study demonstrates that UROMOL molecular classes of NMIBC are associated with distinct TMEs, revealing biologically meaningful differences in immune infiltration and stromal composition.

利益披露 Disclosure

S. Xu, Johnson & Johnson Employment, Stock. M. H. V. Byrne, None. J. Zhang, Johnson & Johnson Employment, Stock. A. Alalti, None.. D. Agarwal, None. N. Beeharry, Johnson & Johnson Employment, Stock. O. Chornoguz, Johnson & Johnson Employment, Stock. K. Dooley, None.. K. Lee, None. S. Li, Johnson & Johnson Employment, Stock. G. Walia, Johnson & Johnson Employment, Stock. T. Mansi, Johnson & Johnson Employment, Stock. J. Greshock, Johnson & Johnson Employment, Stock. C. Dendrou, None. F. Hamdy, NIHR, Prostate Cancer UK ). British Journal of Urology International, UK Policy Advisory Board, Intuitive Surgical Other, Personal Fees. L. Browning, NHSX Artificial Intelligence in Health and Care Award (ArticulatePro) ). D. J. Woodcock, None. P. Wilkinson, Johnson & Johnson Employment, Stock. S. Thomas, Johnson & Johnson Employment, Stock.

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