中国肺癌杂志2025，Vol.28Issue(11)：807-817,11.DOI:10.3779/j.issn.1009-3419.2025.106.31
免疫分型对非小细胞肺癌新辅助疗效的影响及机制
Influence and Mechanism of Immunophenotyping on the Efficacy of Neoadjuvant Therapy in Non-small Cell Lung Cancer
摘要
Abstract
Background and objective The low response rate to immunotherapy can be partially attributed to tumor immune escape mechanisms arising from the heterogeneous tumor microenvironment.This study aims to determine the impact of inflammatory non-small cell lung cancer(NSCLC)on the efficacy of neoadjuvant immunotherapy combined with chemotherapy at the histological level,and to investigate the predictive value of specific CD8+and CD4+T cell numbers,as well as spatial interactions,in treatment response.Methods A retrospective study included 43 patients with NSCLC who underwent neoadjuvant immunotherapy combined with chemotherapy at Shandong Cancer Hospital from January 2021 to June 2023.Preoperative biopsy specimens were collected and subjected to multiplex immunofluorescence staining[CD8/programmed cell death protein 1(PD-1)/T cell immunoglobulin and mucin-domain containing protein 3(TIM-3)/CD4/forkhead box protein 3(FoxP3)/cytokeratin(CK)/4',6-diamidino-2-phenylindole(DAPI)].InForm software was used to per-form tissue segmentation(epithelial and stromal regions)and quantify the density and spatial proximity of tumor cells,CD8+T cells and their subsets(cytotoxic,pre-exhausted and exhausted),as well as CD4+T cells and their subsets(conventional and regulatory).NSCLC was classified into three subtypes based on the relative infiltration levels of CD8+T cells in both the epi-thelial and stromal compartments:inflamed(both compartments>10/1000),excluded(epithelial compartment<10/1000 and stromal compartment>10/1000),and desert(both compartments<10/1000).The Kolmogorov-Smirnov test,Fisher's exact test,Mann-Whitney U test and Logistic regression were used to identify factors associated with major pathological response(MPR).Results Inflamed,excluded,and desert NSCLC accounted for 65.1%,27.9%and 7.0%,respectively.Compared with patients with non-inflamed NSCLC,those with inflamed NSCLC exhibit a higher MPR rate(71.4%vs 33.3%,P=0.016).Both univari-ate and multivariate Logistic regression analyses confirmed that the inflamed subtype is an independent protective factor against the acquisition of MPR in NSCLC patients(OR=0.20,95%CI:0.05-0.74,P=0.020;adjusted OR=0.17,95%CI:0.03-0.80,P=0.030).Analysis of the spatial distance between CD8+and CD4+T cells within the epithelial regions of inflamed NSCLC revealed that the effective density of cytotoxic CD8+T cells within a 30 μm radius of regulatory CD4+T cells was lower in the MPR group than in the non-MPR group(0.00 vs 0.33,P=0.037).Conclusion Patients with inflamed NSCLC demonstrate superior efficacy when receiving neoadjuvant immunotherapy combined with chemotherapy.This may be due to reduced prox-imity between regulatory CD4+T cells and cytotoxic CD8+T cells.关键词
肺肿瘤/免疫浸润分型/新辅助免疫治疗/空间接近性Key words
Lung neoplasms/Immune phenotypes/Neoadjuvant immunotherapy/Spatial proximity引用本文复制引用
伍力,杨丽颖,赵苗青,孙健,曹芳菡,陈千惠,孙晓蓉,邢力刚..免疫分型对非小细胞肺癌新辅助疗效的影响及机制[J].中国肺癌杂志,2025,28(11):807-817,11.基金项目
本研究受癌症、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)、国家自然科学基金面上项目(No.82172866,No.82373424)、山东省科学技术厅纵向项目(No.2021CXGC011102)和山东省肿瘤医院学科集群创新工程项目(No.GF002)资助 This study was supported by the grants from National Key Science and Technology Project for the Prevention and Treatment of Cancer,Cardiovascular and Cerebrovascular Diseases,Respiratory Diseases,and Metabolic Diseases(No.2024ZD0525900)(to Ligang XING),National Natural Science Foundation of China(No.82172866,to Ligang XING （No.2024ZD0525900）
No.82373424,to Xiaorong SUN),Department of Science&Technology of Shandong Province(No.2021CXGC011102)(to Ligang XING)and Collaborative Academic Innovation Project of Shandong Cancer Hospital(No.GF002)(to Ligang XING). （No.2021CXGC011102）
