PO.TB10.02 · 肿瘤生物学
器官特异性的免疫和代谢程序塑造 MSS 结直肠癌转移灶的空间微环境
Organ-specific immune and metabolic programs shape spatial microenvironments in MSS colorectal cancer metastases
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：我们此前对 MSS 转移性结直肠癌（mCRC）的空间分析揭示了不同转移部位间免疫浸润的器官特异性差异（Ye 等，Cancer Res Commun，2023）。在此基础上，我们扩大了队列，并应用高通量空间转录组和蛋白质组平台，以刻画区域和器官依赖性的微环境程序。
方法：使用 GeoMx WTA（70 份标本）在恶性、基质、侵袭边缘、远端和 TLS 相关区域进行空间转录组分析。使用 56 重 CODEX 空间蛋白质组学面板（120 份标本）进行全肿瘤多重成像，以可视化免疫和基质结构。
结果：空间区室是转录变异的主要驱动因素，来自不同器官的恶性上皮区域紧密聚集在一起，并与正常结肠绒毛上皮和基质明显分离。肝脏外缘和远端区域形成了一个与其他器官类似区域分开的转录组簇，表明存在强烈的肝脏相关印记。在这一区域定义的结构内，GSEA 揭示了一致的器官特异性原型。原发结肠通常表现出中等的免疫和代谢程序。肝转移在各区域表现出广泛的代谢激活，包括脂质和氨基酸代谢、线粒体和过氧化物酶体活性以及补体相关特征，反映了一个经代谢调节的肝脏微环境。肺转移与免疫富集的基质、边缘和远端区域相关，以强烈的 NK 细胞细胞毒性、T 细胞分化、细胞因子信号传导、黏膜样免疫网络和抗病毒通路为标志。腹膜转移表现出代谢和免疫学上沉寂的肿瘤核心，而外缘和远端区域则富集脂质和类固醇代谢以及 ECM 和间皮激活，与富含脂质、免疫贫乏的腹膜微环境一致。初步 CODEX 观察结果与这些模式大体一致。肺转移常表现出丰富的 T 细胞浸润；肝转移表现为淋巴细胞在肿瘤边界积聚而肿瘤中心髓系富集；腹膜转移则呈现致密的基质或纤维化结构，肿瘤内淋巴细胞有限。
结论：高通量空间分析揭示了 MSS mCRC 中不同的器官强加的微环境程序。肝转移采用高度代谢和补体相关的微环境，肺转移表现出强烈的瘤周免疫活性，而腹膜转移则在富含脂质但免疫低下的环境中发展。这些发现凸显了各器官如何塑造转移生态，并可能指导部位适配的治疗策略。
查看英文原文 English abstract
Background : Our previous spatial analysis of MSS metastatic colorectal cancer (mCRC) revealed organ-specific differences in immune infiltration across metastatic sites (Ye et al., Cancer Res Commun , 2023). Building on that work, we expanded the cohort and applied high-plex spatial transcriptomic and proteomic platforms to characterize region- and organ-dependent microenvironmental programs.
Methods: Spatial transcriptomic profiling using the GeoMx WTA (70 specimens) was performed across malignant, stromal, invasive-margin, distal, and TLS-associated regions. A 56-plex CODEX spatial proteomic panel (120 specimens) was used for whole-tumor multiplex imaging to visualize immune and stromal architecture.
Results: Spatial compartment was the primary driver of transcriptional variation, with malignant epithelial regions from different organs clustering closely together and separating distinctly from normal colon villus epithelium and stroma. Liver outer-margin and distal regions formed a separate transcriptomic cluster from analogous regions in other organs, indicating a strong liver-associated imprint. Within this region-defined structure, GSEA revealed coherent organ-specific archetypes. Primary colon generally showed intermediate immune and metabolic programs. Liver metastases showed broad metabolic activation across regions, including lipid and amino-acid metabolism, mitochondrial and peroxisomal activity, and complement-related signatures, reflecting a metabolically conditioned liver niche. Lung metastases were associated with immune-enriched stromal, margin, and distal regions, marked by strong NK-cell cytotoxicity, T cell differentiation, cytokine signaling, mucosal-like immune networks, and antiviral pathways. Peritoneal metastases showed metabolically and immunologically quiet tumor cores, while outer and distal regions were enriched for lipid and steroid metabolism, and ECM and mesothelial activation, consistent with a lipid-rich, immune-poor peritoneal niche. Preliminary CODEX observations were broadly consistent with these patterns. Lung metastases often showed abundant T-cell infiltration; liver metastases showed lymphocytes accumulating at tumor boundaries with myeloid-enriched tumor centers; and peritoneal metastases displayed dense stromal or fibrotic architecture with limited intratumoral lymphocytes.
Conclusions: High-plex spatial profiling reveals distinct organ-imposed microenvironmental programs in MSS mCRC. Liver metastases adopt a highly metabolic and complement-associated niche, lung metastases display strong peritumoral immune activity, and peritoneal metastases develop within a lipid-rich but immune-low environment. These findings highlight how each organ shapes metastatic ecology and may guide site-adapted therapeutic strategies.
利益披露 Disclosure
J. Ye, None..
C. A. Egelston, None..
C. Wang, None.