PO.TB10.08 · 肿瘤生物学
结直肠癌微环境的空间结构及其与免疫检查点抑制剂反应的关系
Spatial architectures of colorectal cancer microenvironment underlying immune checkpoint inhibitor response
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
结直肠癌（CRC）仍是癌症死亡的主要原因之一。免疫检查点抑制剂（ICI）是最有效的系统性疗法之一，但仅使一部分MSI-H/MMRd患者获益。为研究肿瘤-免疫-基质的空间组织如何促成异质性的治疗反应，我们使用带有1,000基因单细胞面板的CosMx空间分子成像仪（SMI），对来自接受PD-1抑制剂pembrolizumab治疗（n=10）和未经治疗（n=14）患者的FFPE CRC组织进行了分析。经过图像处理和细胞分割后，通过无监督Leiden聚类、基因模块评分以及使用公共CRC单细胞图谱的有监督InsituType预测对细胞状态进行注释，随后进行空间分析，包括生态位识别、邻域富集、基于距离的度量和配体-受体推断。在24例患者中（性别分布均衡；I-IV期；中位年龄66.5岁），与未经治疗的肿瘤相比，ICI治疗的肿瘤表现出所有CD8⁺ T细胞亚群、CXCL8⁺癌症相关成纤维细胞（CAF）、肌成纤维细胞以及多样的巨噬细胞和中性粒细胞群体的频率明显更高，同时CMS1样恶性细胞的比例更高。从头非负矩阵分解（NMF）揭示了八个肿瘤内在程序，其中炎症/MHC-II、I型IFN/抗原呈递和固有炎症程序在ICI暴露的肿瘤中富集，而侵袭/血管生成、增殖/应激和CEA高表达程序则表征未经治疗的肿瘤。空间映射揭示了两种反复出现的结构：以T-B淋巴细胞聚集及局灶性LTB和CXCL13表达为标志、富含三级淋巴结构（TLS）的免疫浸润型肿瘤，以及表现出基质包裹、免疫混合有限并初步富集CAF-免疫抑制性配体-受体回路的成纤维细胞主导型肿瘤。总之，这些发现描绘了具有不同肿瘤-免疫通讯状态的炎症型与纤维化型CRC微环境。将空间特征与临床反应相整合，将有助于为基于ICI的治疗进行精细化分层，并将TLS密度、CAF分布模式和特定配体-受体模块提名为预测或调节治疗反应性的候选空间生物标志物。
查看英文原文 English abstract
Colorectal cancer (CRC) remains a leading cause of cancer mortality. Immune checkpoint inhibitors (ICI) are among the most effective systemic therapies, yet they benefit only a subset of MSI-H/MMRd patients. To investigate how spatial tumor-immune-stromal organization contributes to heterogeneous treatment responses, we profiled FFPE CRC tissues from PD-1 inhibitor pembrolizumab-treated (n=10) and treatment-naïve (n=14) patients using the CosMx Spatial Molecular Imager (SMI) with a 1,000-gene single-cell panel. After image processing and cell segmentation, cell states were annotated through unsupervised Leiden clustering, gene-module scoring, and supervised InsituType prediction using a public CRC single-cell atlas, followed by spatial analyses including niche identification, neighborhood enrichment, distance-based metrics, and ligand-receptor inference. Across 24 patients (balanced sex distribution; stages I-IV; median age 66.5), ICI-treated tumors exhibited markedly higher frequencies of all CD8⁺ T cell subsets, CXCL8⁺ cancer-associated fibroblasts (CAFs), myofibroblasts, and diverse macrophage and neutrophil populations compared with treatment-naïve tumors, alongside higher proportions of CMS1-like malignant cells. De novo nonnegative matrix factorization (NMF) revealed eight tumor-intrinsic programs, with Inflammatory/MHC-II, Type I IFN/Antigen Presentation, and Innate Inflammatory programs enriched in ICI-exposed tumors, whereas Invasion/Angiogenesis, Proliferation/Stress, and CEA-high programs characterized untreated tumors. Spatial mapping uncovered two recurrent architectures: immune-infiltrated tumors enriched for tertiary lymphoid structures (TLSs) marked by T-B lymphocyte aggregates and focal LTB and CXCL13 expression, as well as fibroblast-dominated tumors demonstrating stromal encapsulation, limited immune intermixing, and preliminary enrichment of CAF-immune suppressive ligand-receptor circuits. Together, these findings delineate inflamed versus fibrotic CRC microenvironments with distinct tumor-immune communication states. Integration of spatial features with clinical response will support refined stratification for ICI-based therapy and nominate TLS density, CAF patterning, and specific ligand-receptor modules as candidate spatial biomarkers for predicting or modulating treatment responsiveness.
利益披露 Disclosure
C. Liu,
Sanofi S.A. ).
H. Yin,
Sanofi S.A. ).
J. Lee,
Sanofi S.A. Employment.
J. Tessier,
Sanofi S.A. Employment.
J. Kim,
Sanofi S.A. ).
D. Jackson,
Sanofi S.A. Employment.
A. Hadjipanayis,
Sanofi S.A. Employment.
O. Elemento,
Sanofi S.A. ).
Freenome Holdings, Inc. Other, Scientific advisor and equity holder.
Owkin Other, Scientific advisor and equity holder.
Volastra Therapeutics, Inc. Other, Scientific advisor and equity holder.
OneThree Biotech, Inc. Other, Scientific advisor and equity holder.