PO.CL05.09 · 临床研究
整合空间转录组学揭示驱动HNSCC转移的EMT驱动型免疫调控程序
Integrative spatial transcriptomics reveals EMT-driven immune regulatory programs underlying metastasis in HNSCC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
头颈部鳞状细胞癌(HNSCC)是一种全球高发的恶性肿瘤。标准治疗通常包括手术切除、放疗和化疗。然而，对于复发或远处转移、已无法进行手术或放疗的患者，由靶向药物联合化疗或免疫检查点抑制剂(ICI)构成的全身治疗成为主要治疗手段。尽管取得了这些进展，临床结局仍不尽如人意，凸显了阐明免疫细胞组成和功能状态在侵袭性或转移性肿瘤的肿瘤微环境(TME)中如何发生改变的迫切需求。这些认识对于提高ICI在HNSCC中的疗效至关重要。本研究的目的是表征不同HNSCC标本间TME组成的变化。我们采用GeoMx数字空间分析仪(DSP)进行高分辨率、影像引导的空间转录组分析。通过比较富集于肿瘤侵袭前沿的EMT相关基因特征，我们发现典型EMT标志物——包括FN1、CD44和ITGB1——显著上调。为了进一步剖析与ITGB1高表达肿瘤细胞相关的调控程序，我们应用了单细胞调控网络推断与聚类分析(SCENIC)，揭示了不同的调控子活性。值得注意的是，IRF相关信号传导成为ITGB1高表达EMT肿瘤群体中的一条主要下游调控通路。随后，我们采用整合空间组学(10x Visium和10x Xenium)方法分析HNSCC组织，并鉴定出肿瘤EMT状态的清晰转录轨迹。为了直接评估EMT高表达肿瘤细胞如何调节周围免疫细胞，我们进行了NicheNet配体-受体分析，揭示了塑造恶性HNSCC免疫格局的配体-受体相互作用发生了明显改变。总的来说，这些发现为EMT驱动的免疫抑制提供了机制层面的见解，并突出了可指导头颈癌患者个体化治疗策略的可干预TME特征。
查看英文原文 English abstract
Head and neck squamous cell carcinoma (HNSCC) is a globally prevalent malignancy. Standard treatment typically involves surgical resection, radiotherapy, and chemotherapy. However, for patients with recurrent or distantly metastatic disease for whom surgery or radiation is no longer feasible, systemic therapy consisting of targeted agents combined with chemotherapy or immune checkpoint inhibitors (ICI) becomes the mainstay of management. Despite these advances, clinical outcomes remain suboptimal, underscoring the urgent need to elucidate how immune cell composition and functional states are altered within the tumor microenvironment (TME) of aggressive or metastatic tumors. Such insights are essential for improving the therapeutic effectiveness of ICIs in HNSCC. The objective of this study was to characterize TME compositional changes across diverse HNSCC specimens. We employed the GeoMx Digital Spatial Profiler (DSP) to perform high-resolution, imaging-guided spatial transcriptomic profiling. By comparing EMT-related gene signatures enriched at the invasive tumor front, we identified significant upregulation of canonical EMT markers-including FN1, CD44, and ITGB1. To further dissect the regulatory programs associated with ITGB1-high tumor cells, we applied Single-Cell Regulatory Network Inference and Clustering (SCENIC), which revealed distinct regulon activities. Notably, IRF-associated signaling emerged as a major downstream regulatory pathway in ITGB1-high EMT tumor populations. Subsequently, we analyzed HNSCC tissues using integrative spatial-omics (10x Visium and 10x Xenium) approaches and identified a clear transcriptional trajectory of tumor EMT states. To directly assess how EMT-high tumor cells modulate surrounding immune cells, we performed NicheNet ligand-receptor analysis, which revealed pronounced alterations in ligand-receptor interactions shaping the immune landscape of malignant HNSCC. Collectively, these findings provide mechanistic insights into EMT-driven immune suppression and highlight actionable TME features that could guide personalized therapeutic strategies for patients with head and neck cancer.
利益披露 Disclosure
C. Chung, None..
H. Yu, None..
M. Yang, None.