PO.TB10.12 · 肿瘤生物学
缺氧驱动的上皮重编程升高CD46并促进免疫荒漠型NSCLC中的血管生成拟态
Hypoxia-driven epithelial reprogramming elevates CD46 and promotes vasculogenic mimicry in immune-desert NSCLC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：免疫荒漠型非小细胞肺癌（NSCLC）尽管存在肿瘤抗原，但由于T细胞浸润不良，对免疫治疗构成重大挑战。虽然这些肿瘤中的免疫抑制已被充分认识，但上皮和基质区室对塑造肿瘤微环境（TME）的贡献仍未明确界定。
方法：我们分析了60例肺腺癌（LUAD）肿瘤的批量RNA-seq图谱，并使用T细胞炎症特征将其分类为免疫荒漠型或炎症型。进一步使用单细胞RNA测序（scRNA-seq）对匹配的肿瘤进行表征，以解析TME内的上皮、基质和免疫区室。关键发现通过公共数据集、患者标本的免疫组织化学（IHC）以及CRISPR/Cas9编辑细胞系中的功能实验进行验证。
结果：与免疫浸润型上皮细胞相比，荒漠型上皮细胞富集于补体级联、缺氧、胆固醇稳态和EMT通路，而OXPHOS和抗原加工程序被下调。调控子分析鉴定出XBP1为荒漠型上皮细胞中的关键转录因子，其靶向驱动荒漠富集通路的其他基因，包括CD46、补体调节模块以及参与髓系募集和免疫逃逸的细胞因子/趋化因子。这些结果提示，荒漠型上皮细胞处于应激适应的可塑状态。在内皮谱系中，荒漠型肿瘤表现出较低的PCV评分（一种与T细胞浸润相关的指标），同时表达癌症干性相关基因的上皮样内皮细胞比例增加。在该程序的调控因子中，缺氧诱导性转录因子ELF3在血管拟态（VM）相关细胞中强烈上调。IHC证实荒漠型肿瘤上皮表面存在稳健的CD46表达。值得注意的是，CD46高表达的NSCLC细胞系较CD46低表达细胞系形成显著更多的VM网络。公共数据集的分析进一步证实了CD46表达、缺氧信号、VM富集、免疫浸润和免疫治疗反应之间的负相关关系，与这些程序在介导免疫排斥中的作用一致。
结论：这些发现表明，部分由XBP1驱动的缺氧相关上皮应激程序升高CD46并支持VM相关可塑性，形成免疫荒漠状态特有的免疫和结构双重屏障。总之，这些结果勾勒出缺氧适应性上皮和内皮转变如何重组荒漠型肿瘤的结构，并有助于解释其对T细胞浸润的持续抵抗，凸显了在解读荒漠表型时将结构重塑与免疫抑制一并考虑的价值。
查看英文原文 English abstract
Introduction: Immune-desert non-small cell lung cancer (NSCLC) presents a major challenge for immunotherapy due to poor T-cell infiltration despite the presence of tumor antigens. While immune suppression in these tumors is well recognized, the contributions of epithelial and stromal compartments to shaping the tumor microenvironment (TME) remain poorly defined.
Methods: We analyzed bulk RNA-seq profiles from 60 lung adenocarcinoma (LUAD) tumors and classified them as immune-desert or inflamed using a T-cell inflammed signature. Matched tumors were further characterized using single-cell RNA sequencing (scRNA-seq) to dissect epithelial, stromal, and immune compartments within the TME. Key findings were validated using public datasets, immunohistochemistry (IHC) of patient specimens, and functional assays in CRISPR/Cas9-edited cell lines.
Results: Compared with immune-infiltrated epithelial cells, desert epithelial cells were enriched in complement cascade, hypoxia, cholesterol homeostasis, and EMT pathways, while OXPHOS and antigen-processing programs were downregulated. Regulon analysis identified XBP1 as a key transcription factor in desert epithelial cells, which targeted other genes driving desert-enriched pathways, including CD46, complement-regulatory modules, and cytokines/chemokines involved in myeloid recruitment and immune evasion. These results suggest that desert epithelial cells are in an stress-adapted, plastic state. In the endothelial lineage, Desert tumors exhibited reduced PCV scores, a metric associated with T-cell infiltration, alongside an increased proportion of Epi-like endothelial cells expressing cancer stemness-related genes. Among regulators of this program, ELF3, a hypoxia-inducible transcription factor, was strongly upregulated in vascular mimicry (VM)-associated cells. IHC confirmed robust CD46 expression on epithelial surfaces of Desert tumors. Notably, CD46-high NSCLC lines formed significantly more VM networks than CD46-low lines. Analyses of public datasets further corroborated inverse relationships among CD46 expression, hypoxia signaling, VM enrichment, immune infiltration, and immunotherapy response, consistent with a role for these programs in mediating immune exclusion.
Conclusions These findings indicate that hypoxia-linked epithelial stress programs, driven in part by XBP1, elevate CD46 and support VM-related plasticity, forming both immunologic and structural barriers characteristic of the immune-desert state. Together, these results outline how hypoxia-adapted epithelial and endothelial transitions reorganize the architecture of Desert tumors and help explain their persistent resistance to T-cell infiltration, highlighting the value of considering structural remodeling alongside immune suppression when interpreting the desert phenotype.
利益披露 Disclosure
M. Kim, None.