PO.CL01.02 · 临床研究
MUC5AC表达界定胰腺导管腺癌中一种免疫炎症型但功能受限的肿瘤微环境
MUC5AC expression defines an immune-inflamed but functionally restrained tumor microenvironment in pancreatic ductal adenocarcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胰腺导管腺癌（PDAC）对免疫检查点抑制剂（ICI）高度耐药，主要归因于免疫排斥性和基质致密的微环境。MUC5AC是一种在PDAC中异常表达的凝胶形成型黏蛋白，与肿瘤进展和免疫逃逸有关。为界定其在塑造肿瘤免疫格局中的作用，我们研究了MUC5AC高表达与MUC5AC低表达PDAC的转录组通路和免疫浸润特征。分析了来自TCGA、ICGC和GEO PDAC队列（N=1047）的转录组数据。采用基因本体论（Gene Ontology）和KEGG评估差异表达和通路富集。为确保跨平台稳健性，使用多种转录组解卷积算法推断免疫细胞浸润，包括CIBERSORT、CIBERSORT-Abs、EPIC、MCPcounter、quanTIseq、xCell、ESTIMATE和TIMER。使用中位数临界值将免疫调节基因和免疫抑制基因的表达与MUC5AC水平进行相关性分析，并进行跨队列验证。MUC5AC高表达肿瘤显示脂质和聚糖代谢、糖基转移酶活性、细胞外囊泡分泌以及细胞骨架/黏附通路的富集，与代谢重编程和基质重塑一致。尽管KEGG免疫通路（T细胞受体、B细胞受体、NK细胞毒性、趋化因子信号）在转录水平上被激活，但功能特征证据提示免疫抑制。免疫浸润分析显示，MUC5AC高表达肿瘤与更高的Tregs、静息记忆CD4⁺ T细胞、M0巨噬细胞、静息自然杀伤（NK）细胞、记忆B细胞、浆细胞和静息树突状细胞显著相关（p<0.05），并与更低的CD8⁺ T细胞、活化NK细胞、滤泡辅助T细胞、活化记忆CD4⁺ T细胞、M1巨噬细胞、初始B细胞、γδ T细胞和M2巨噬细胞相关。重要的是，免疫调节因子分析显示抑制性分子存在显著差异（p<0.05），与PD-L1、LGALS9、IL10/IL10RB、TGFB1/TGFBR1和IDO1呈正相关，与PD-1、PD-L2、CTLA4、LAG3和TIM-3呈负相关。因此，MUC5AC高表达PDAC表现出一种"免疫炎症型但功能受限"的表型，其特征为免疫信号被激活但以基质、代谢和配体驱动的抑制性程序占主导。MUC5AC可作为免疫排斥的生物标志物，指导基于ICI治疗的患者分层。
查看英文原文 English abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to immune checkpoint inhibitors (ICIs), largely due to an immune-excluded and stromal-dense microenvironment. MUC5AC, a gel-forming mucin aberrantly expressed in PDAC, is implicated in tumor progression and immune evasion. To define its role in shaping the tumor immune landscape, we investigated transcriptomic pathway, and immune infiltration features of MUC5AC-high versus MUC5AC-low PDACs. Transcriptomic data from TCGA, ICGC, and GEO PDAC cohorts (N=1047) were analyzed. Differential expression and pathway enrichment were assessed using Gene Ontology and KEGG. To ensure cross-platform robustness, immune cell infiltration was inferred using multiple transcriptomic deconvolution algorithms, including CIBERSORT, CIBERSORT-Abs, EPIC, MCPcounter, quanTIseq, xCell, ESTIMATE, and TIMER. Expression of immunomodulator and immune inhibitory genes was correlated with MUC5AC levels using median cut-offs, with cross-cohort validation. MUC5AC-high tumors showed enrichment of lipid and glycan metabolism, glycosyltransferase activity, extracellular vesicle secretion, and cytoskeletal/adhesion pathways, consistent with metabolic rewiring and stromal remodeling. Although KEGG immune pathways (T cell receptor, B cell receptor, NK cytotoxicity, chemokine signaling) were transcriptionally activated, functional signature evidence indicated immune suppression. Immune infiltration analysis revealed that MUC5AC-high tumors had significant associations (p<0.05) with higher Tregs, resting memory CD4⁺ T cells, M0 macrophages, resting natural killer (NK) cells, memory B cells, plasma cells, and resting dendritic cells, and lower CD8⁺ T cells, activated NK cells, follicular helper T cells, activated memory CD4⁺ T cells, M1 macrophages, naïve B cells, gammadelta T cells, and M2 macrophages . Importantly, immunomodulator profiling demonstrated significant differences (p<0.05) in inhibitory molecules, with positive associations with PD-L1, LGALS9, IL10/IL10RB, TGFB1/TGFBR1, and IDO1, and negative associations with PD-1, PD-L2, CTLA4, LAG3, and TIM-3.Thus, MUC5AC-high PDAC exhibits an “immune-inflamed but functionally restrained” phenotype, characterized by immune signaling engagement but dominance of stromal, metabolic, and ligand-driven suppressive programs. MUC5AC may serve as a biomarker of immune exclusion, guiding patient stratification for ICI-based therapies.
利益披露 Disclosure
A. Manne,
Ipsen Other, Advisory board.
W. Yang, None..
Y. Guo, None.
V. Sahai,
Actuate Therapeutics ).
Boehingrer Ingram ).
Bristol-myeres Squibb ).
Vlovis ).
Elicio ).
Esanik ).
Exelixis ).
Fibrinogen ).
Ipsen ).
Jazz ).
Cornerstone ).
Relay ).
Repare ).
RevMed ).
Servier ).
Systimmune ).
Trasnsthera ).
Astrazeneca Other, COnsultant.
Autem Other, Consultant.
Amplify Other, Consultant.
P. Bajpai, None..
Y. Bao, None..
M. Niazi, None..
A. Leyva, None.