非小细胞肺癌中模拟芯针活检尺寸下的瘤内免疫异质性：一项探索性研究
Intratumor immune heterogeneity across simulated core biopsy sizes in non-small cell lung cancer: an exploratory study.
作者
作者单位
- Department of Radiation Oncology (Maastro), GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands.
- Data Science Institute, Center for Statistics Hasselt University, Hasselt, Belgium.
- Department of Pathology, KU Leuven-University of Leuven, University Hospitals Leuven, Leuven, Belgium.
- Department of Pathology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands.
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium.
- Department of Pulmonary Diseases, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands.
- Respiratory Oncology Unit (Pulmonology), University Hospitals Leuven, Leuven, Belgium.
- Department of Radiation Oncology, University Hospitals Leuven, Leuven, Belgium.
摘要
中文
免疫检查点阻断（ICB）广泛用于治疗非小细胞肺癌（NSCLC）患者。然而，瘤内（免疫）异质性可能显著影响ICB的治疗效果。目前尚不清楚更大尺寸的芯针活检是否能更好地代表瘤内异质性。本研究旨在探讨不同模拟活检芯尺寸下选定免疫相关参数的个体内和个体间异质性。在这项探索性前瞻性队列研究中，纳入了接受根治性手术、伴或不伴新辅助化疗或放化疗的I-III期NSCLC患者。使用四重免疫荧光染色（CD31、Ki67、CD4、CD8、CD68、FOXP3、PD-L1、广谱细胞角蛋白和DAPI）评估切除肿瘤标本的瘤内免疫异质性。使用数字图像模拟直径从1毫米到4毫米不等的活检芯。使用四分位离散系数（QCD）量化250个随机选择的亚区域（每个芯尺寸）的异质性。分析了29例患者的肿瘤标本，其中10例接受过新辅助治疗。所有标志物的瘤内QCD值随着模拟活检芯直径的增大而显著降低。尽管如此，程序性死亡配体1（PD-L1）仍存在显著的空间异质性，即使4毫米模拟活检芯中，58.8%的患者仍显示异质性分布。较大的活检芯尺寸与大多数免疫标志物的瘤内异质性降低相关，提示能更好地反映整个肿瘤的免疫景观。然而，即使在较大芯中，PD-L1表达仍存在空间异质性。需要在更大的前瞻性队列研究中进一步验证，以确定异质性指标的转化相关性，并更好地指导常规临床实践中的活检取样策略。
English
Immune checkpoint blockade (ICB) is widely used to treat patients with non-small cell lung cancer (NSCLC). However, intratumor (immune) heterogeneity may significantly impact the therapeutic efficacy of ICBs. It remains unknown whether larger core biopsies better represent the intratumor heterogeneity. This study aimed to explore the intra- and interpatient heterogeneity of selected immune-related parameters on varying simulated biopsy core sizes. In this exploratory prospective cohort study, patients with stage I-III NSCLC who had undergone curative-intent surgery, with or without neoadjuvant chemotherapy or chemoradiation, were enrolled. Intratumor immune heterogeneity was assessed using quadruple immunofluorescence stainings (CD31, Ki67, CD4, CD8, CD68, FOXP3, PD-L1, Pan-keratin, and DAPI) on resected tumor specimens. Digital images were used to simulate biopsy cores ranging from 1- to 4-mm in diameter. Heterogeneity was quantified using the quartile coefficient of dispersion (QCD) across 250 randomly selected subregions per core size. Tumor specimens from 29 patients were analyzed, including 10 patients who had received neoadjuvant therapy. Intratumor QCD values decreased significantly with increasing simulated biopsy core diameter for all markers. Nonetheless, substantial spatial heterogeneity persisted for programmed death-ligand 1 (PD-L1), with 58.8% of patients showing heterogeneous distribution, even in 4-mm simulated biopsy cores. Larger biopsy core sizes were associated with reduced intratumor heterogeneity for most immune markers, suggesting a better reflection of the tumor immune landscape of the whole tumor. However, PD-L1 expression remained spatially heterogeneous even in larger cores. Further validation in larger prospective cohort studies will be essential to determine the translational relevance of heterogeneity metrics and to better inform biopsy sampling strategies in routine clinical practice.
分类与指标
- 研究类型
- 临床研究
- 病种
- 肺癌
- JCR 分区
- Q2
- 影响因子
- 3.4
- 新锐分区
- 3区