中国肺癌杂志2026，Vol.29Issue(2)：115-123,9.DOI:10.3779/j.issn.1009-3419.2026.106.05
非小细胞肺癌中HIF-1α细胞亚群对淋巴结转移和术后复发的影响
Impact of HIF-1α-expressing Cellular Subpopulations on Lymph Node Metastasis and Postoperative Recurrence in Non-small Cell Lung Cancer
摘要
Abstract
Background and objective Non-small cell lung cancer(NSCLC)is associated with a high rate of post-operative recurrence,and conventional tumor-node-metastasis(TNM)staging does not fully reflect its biological heterogene-ity.Hypoxia-inducible factor-1alpha(HIF-1α)plays a critical role in tumor progression and remodeling of the tumor immune microenvironment.However,the spatial distribution of HIF-1α and its prognostic significance in the context of different lymph node metastatic states remain unclear.This study aimed to investigate the densities of HIF-1α-expressing tumor cells,CD4+T cells,and CD8+T cells in the primary tumors of NSCLC patients,and to assess their associations with lymph node metastasis and post-operative recurrence.Methods 256 formalin-fixed paraffin-embedded primary tumor specimens from NSCLC patients who underwent radical resection at Shandong First Medical University Affiliated Cancer Hospital between January 1,2014 and December 31,2018 were retrospectively collected.Tissue microarrays containing both tumor center(TC)and invasive margin(IM)regions were constructed and multiplex immunofluorescence staining[HIF-1α/CD4/CD8/cytokeratin(CK)/4',6-diamidino-2-phenylindole(DAPI)]were performed to quantitatively analyze the densities of HIF-1α-expressing tumor cells(HIF-1α+CK+),HIF-1α+CD4+T cells and HIF-1α+CD8+T cells.Mann-Whitney U tests were used to compare cellular density differences between N0 versus N1-2 groups and N1 versus N2 subgroups,while Cox proportional hazards regression models were employed to identify critical recurrence-associated factors.Results The study ultimately included 256 patients with stage IA-IIIB NSCLC,with a median follow-up duration of 37.05 months,during which 87 cases(34.0%)expe-rienced recurrence.Comparative analysis revealed that in both TC and IM regions,the N1-2 group exhibited significantly higher densities of HIF-1α+CK+cells(P values:0.039 and<0.001,respectively)and lower densities of HIF-1α+CD8+cells(both P values:<0.001)compared to the N0 group,while no statistically significant differences were observed in the densities of HIF-1α+CK+cells,HIF-1α+CD4+cells,or HIF-1α+CD8+cells between N1 and N2 subgroups within either TC or IM regions(all P>0.05).Multivariate Cox regression analysis showed that,among N0 patients,a low density of HIF-1α+CD8+cells in the TC was an independent risk factor for recurrence in NSCLC patients[hazard ratio(HR)=1.998,95%CI:1.077-3.705,P=0.028].In contrast,among N1 and N2 patients,the densities of HIF-1α+CK+cells,HIF-1α+CD4+T cells,and HIF-1α+CD8+cells in both the TC and IM regions were not significantly associated with NSCLC recurrence.Con-clusion In patients with NSCLC,lymph node metastasis is closely associated with alterations in the densities of HIF-1α-related cellular subpopulations in the primary tumor.A reduced density of HIF-1α+CD8+cells in the TC of the primary lesion is significantly associated with postoperative recurrence in N0-stage NSCLC patients and may serve as a potential immunological marker for postoperative risk strati-fication.关键词
肺肿瘤/无复发生存时间/淋巴结转移/预后/乏氧诱导因子-1α/CD8+T细胞/肿瘤中心Key words
Lung neoplasms/Recurrence-free survival time/Lymph node metastasis/Prognosis/Hypoxia-inducible factor-1alpha/CD8+T cell/Tumor center引用本文复制引用
曹芳菡,陈千惠,杨丽颖,赵苗青,孙晓蓉,邢力刚..非小细胞肺癌中HIF-1α细胞亚群对淋巴结转移和术后复发的影响[J].中国肺癌杂志,2026,29(2):115-123,9.基金项目
本研究受国家自然科学基金项目(No.82373424)和2024年度癌症、心脑血管、呼吸和代谢性疾病防治研究国家科技重大专项(No.2024ZD0525900)资助 This study was supported by the grants from National Natural Science Foundation of China(No.82373424,to Xiaorong SUN)and National Science and Technology Major Special Project for Prevention and Treatment Research of Cancer,Cardiovascular and Cerebrovas-cular Diseases,Respiratory Diseases and Metabolic Diseases,2024(No.2024ZD0525900,to Ligang XING). （No.82373424）
