PO.TB10.01 · 肿瘤生物学

空间转录组学揭示肺癌前病变-腺癌连续过程中肿瘤微环境原型的演变

Spatial transcriptomics reveals evolving tumor microenvironmental archetype along the lung premalignancy-adenocarcinoma continuum

编号 2255 展板 4 时间 4/20 09:00–12:00 区域 Section 33 主讲 Yibo Dai, MS

分会场 Tumorigenesis and Early Microenvironmental Trajectories

查看 PDF 下载 PDF 🔒 查看 / 下载完整 PDF 需登录并开通下载套餐 · 查看套餐 / 开通 AACR 官方页面

作者与单位 Authors & Affiliations

Yibo Dai¹, Fuduan Peng¹, Ansam Sinjab¹, Yunhe Liu¹, Sujuan Yang¹, Lorena I Gomez Bolanos¹, Tieling Zhou¹, Minyue Chen¹, Alejandra G Serrano¹, Jianlong Liao¹, Guangsheng Pei¹, Yang Liu¹, Jiahui Jiang¹, Kyung Serk Cho¹, Kai Yu¹, Jiping Feng¹, Zahraa Rahal¹, Naoe Jimbo², Takuo Hayashi³, Satsuki Kishikawa³, Kazuya Takamochi³, Avrum Spira⁴, Steven M. Dubinett⁵, Tomoo Itoh², Takashi Yao³, Kenji Suzuki³, Stephen G. Swisher¹, Mingyao Li⁶, Junya Fujimoto⁷, Ignacio Wistuba⁸, Jared K. Burks¹, Kadir Caner Akdemir¹, Hind Rafei¹, Katayoun Rezvani¹, Jeffrey N. Myers¹, Humam Kadara¹, Linghua Wang¹

¹UT MD Anderson Cancer Center, Houston, TX,²Kobe University Hospital, Kobe, Japan,³Juntendo University Graduate School of Medicine, Tokyo, Japan,⁴Lung Cancer Initiative at Johnson and Johnson, Boston, MA,⁵UCLA David Geffen School of Medicine, Los Angeles, CA,⁶University of Pennsylvania, Philadelphia, PA,⁷Hiroshima University Hospital, Hiroshima, Japan,⁸Moffitt Cancer Center & Research Institute, Tampa, FL

摘要 Abstract

中文摘要

背景：肺腺癌（LUAD）是全球最致命的癌症类型之一，然而在从癌前病变（PMLs）向LUAD转变过程中肿瘤微环境（TME）原型如何被重塑仍知之甚少。本研究旨在利用空间分辨转录组学，系统表征PML-LUAD连续过程中肿瘤免疫原型的动态演变。方法：使用Visium（spot水平）平台对来自25例配对PML和LUAD患者的56个样本进行空间分析。其中，来自6例患者的12个配对样本还使用Xenium 5K（单细胞分辨率）平台进行了检测。研究了TME细胞组织和相互作用，并定义了不同的空间TME原型。随后，从空间数据中衍生出代表这些微环境结构的特征评分，并在bulk RNA测序队列中进行验证。最后，对来自Gprc5a敲除（Gprc5a-/-）并暴露于烟草衍生亚硝胺酮（NNK）的致癌小鼠模型的连续肺样本进行单细胞RNA测序（scRNA-seq），表征LUAD发生过程中TME原型的动态转变。结果：与PML相比，LUAD表现出癌相关成纤维细胞的扩张，同时伴有成熟三级淋巴结构的瘤内富集和自然杀伤细胞的减少。此外，在LUAD中观察到多种免疫抑制信号，并显示从远端正常区域到肿瘤区域的渐进性上调。总之，这些发现表明恶性进展过程中TME发生动态重塑。TME细胞的空间定位揭示了四种不同的免疫原型，称为LUAD与PML中的免疫表型空间背景分型（IMPACT）。PML以IMPACT-1为主，肿瘤区域富集巨噬细胞，同时伴有瘤内T细胞（亚型1a）或B细胞（亚型1b）的富集。相比之下，LUAD表现为混合淋巴细胞浸润（IMPACT-2）或淋巴细胞排斥（IMPACT-3）。这些亚型显示出不同的分子特征，表现出促肿瘤炎症、免疫激活以及不同免疫逃逸机制的证据。将IMPACT特征应用于bulk RNA测序队列，重现了不同IMPACT亚型的关键免疫特征及其与疾病分期的关联。最后，对Gprc5a-/-致癌小鼠模型肺样本的scRNA-seq分析进一步验证了IMPACT亚型随时间的动态转变。结论：PML-LUAD进展伴随着深刻的TME重编程。通过空间免疫原型对患者进行分层，可能有助于预测疾病发展轨迹并为早期癌症阻断策略提供依据。

查看英文原文 English abstract

Background: Lung adenocarcinoma (LUAD) is one of the most lethal cancer types worldwide, yet how the tumor microenvironmental (TME) archetypes are remodelled during the transition from premalignant lesions (PMLs) to LUAD remains poorly understood. This study aims to systemically characterize the dynamic evolution of tumor immune archetypes across the PML-LUAD continuum using spatially resolved transcriptomics. Methods: Spatial profiling was conducted on 56 samples from 25 patients with paired PMLs and LUADs using the Visium (spot-level) platform. Among them, 12 paired samples from 6 patients were also profiled with the Xenium 5K (single-cell-resolution) platform. TME cellular organizations and interactions were investigated, and distinct spatial TME archetypes were defined. Subsequently, signature scores representing these microenvironmental architectures were derived from spatial data and validated in bulk RNA-sequencing cohorts. Finally, single-cell RNA sequencing (scRNA-seq) was performed on serial lung samples from a carcinogenesis mouse model with Gprc5a knockout ( Gprc5a -/- ) and exposure to nicotine-derived nitrosamine ketone (NNK), and the dynamic transition of TME archetypes during LUAD development was characterized. Results: Compared with PMLs, LUADs displayed an expansion of cancer-associated fibroblasts, alongside intratumoral enrichment of mature tertiary lymphoid structures and depletion of natural killer cells. Additionally, multiple immune-suppressive signals were observed in LUADs and showed progressive upregulation from distal normal to tumor regions . Altogether, these findings indicate dynamic TME remodelling during malignant progression. Spatial mapping of TME cells revealed four distinct immune archetypes, termed IMmune Phenotype spAtial Contextual Typing in LUAD and PML (IMPACT). PMLs were dominated by IMPACT-1, with enrichment of macrophages in the tumor regions, alongside concurrent intratumoral enrichment of T (subtype 1a) or B (subtype 1b) cells. In contrast, LUADs exhibited mixed lymphocyte infiltration (IMPACT-2) or lymphocyte exclusion (IMPACT-3). These subtypes displayed distinct molecular profiles, showing evidence of tumor-promoting inflammation, immune activation, and different mechanisms of immune evasion. IMPACT signatures applied to bulk RNA sequencing cohorts recapitulated key immune features of different IMPACT subtypes and their associations with disease stages. Finally, scRNA-seq analysis on lung samples from the Gprc5a -/- carcinogenesis mouse model further validated the dynamic transition of IMPACT subtypes overtime. Conclusions: PML-LUAD progression is accompanied by profound TME reprogramming. Patient stratifications by spatial immune archetypes may enable predicting disease developmental trajectories and inform strategies for early cancer interception.

利益披露 Disclosure

Y. Dai, None.. A. Sinjab, None.. S. Yang, None.. L. Gomez Bolanos, None.. T. Zhou, None.. M. Chen, None.. A. Serrano, None.. J. Liao, None.. Y. Liu, None.. J. Jiang, None.. J. Feng, None.. Z. Rahal, None.. N. Jimbo, None.. T. Hayashi, None.. S. Kishikawa, None.. K. Takamochi, None.. A. Spira, None.. T. Itoh, None.. T. Yao, None.. K. Suzuki, None.. S. G. Swisher, None.. J. Fujimoto, None.. I. Wistuba, None.. J. K. Burks, None.

← 返回 AACR 2026 检索