Lee Hyunjong, Choi Hongyoon
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
Front Oncol. 2022 Mar 4;12:828505. doi: 10.3389/fonc.2022.828505. eCollection 2022.
As the molecular features of lung adenocarcinoma (LUAD) have been evaluated as a cross-sectional study, the course of tumor characteristics has not been modeled. The temporal evolution of the tumor immune microenvironment (TIME), as well as the clinico-molecular features of LUAD, could provide a precise strategy for immunotherapy and surrogate biomarkers for the course of LUAD.
A pseudotime trajectory was constructed in patients with LUAD from the Cancer Genome Atlas and non-small cell lung cancer radiogenomics datasets. Correlation analyses were performed between clinical features and pseudotime. Genes associated with pseudotime were selected, and gene ontology analysis was performed. F-18 fluorodeoxyglucose positron emission tomography images of subjects were collected, and imaging parameters, including standardized uptake value (SUV), were obtained. Correlation analyses were performed between imaging parameters and pseudotime. Correlation analyses were performed between the enrichment scores of various immune cell types and pseudotime. In addition, correlation analyses were performed between the expression of PD-L1, tumor mutation burden, and pseudotime.
Pseudotime trajectories of LUAD corresponded to clinical stages. Molecular profiles related to cell division and natural killer cell activity were changed along the pseudotime. The maximal SUV of LUAD tumors showed a positive correlation with pseudotime. Type 1 helper T (Th1) cells showed a positive correlation, whereas M2 macrophages showed a negative correlation with pseudotime. PD-L1 expression showed a negative correlation, whereas tumor mutation burden showed a positive correlation with pseudotime.
The estimated pseudotime associated with the stage suggested that it could reflect the clinico-molecular evolution of LUAD. Specific immune cell types in the TIME as well as cell division and glucose metabolism were dynamically changed according to the progression of the pseudotime. As a molecular progression of LUAD, different cellular targets should be considered for immunotherapy.
由于肺腺癌（LUAD）的分子特征已作为一项横断面研究进行了评估，肿瘤特征的发展过程尚未建立模型。肿瘤免疫微环境（TIME）的时间演变以及LUAD的临床分子特征可为免疫治疗提供精确策略，并为LUAD的病程提供替代生物标志物。
在来自癌症基因组图谱和非小细胞肺癌放射基因组学数据集的LUAD患者中构建了一个伪时间轨迹。对临床特征与伪时间进行相关性分析。选择与伪时间相关的基因，并进行基因本体分析。收集受试者的F-18氟脱氧葡萄糖正电子发射断层扫描图像，并获得包括标准化摄取值（SUV）在内的成像参数。对成像参数与伪时间进行相关性分析。对各种免疫细胞类型的富集分数与伪时间进行相关性分析。此外，对程序性死亡受体配体1（PD-L1）的表达、肿瘤突变负荷与伪时间进行相关性分析。
LUAD的伪时间轨迹与临床分期相对应。与细胞分裂和自然杀伤细胞活性相关的分子谱沿伪时间发生变化。LUAD肿瘤的最大SUV与伪时间呈正相关。1型辅助性T（Th1）细胞与伪时间呈正相关，而M2巨噬细胞与伪时间呈负相关。PD-L1表达与伪时间呈负相关，而肿瘤突变负荷与伪时间呈正相关。
与分期相关的估计伪时间表明它可以反映LUAD的临床分子演变。TIME中的特定免疫细胞类型以及细胞分裂和葡萄糖代谢根据伪时间的进展而动态变化。作为LUAD的分子进展，免疫治疗应考虑不同的细胞靶点。
