Background: Tumor microenvironment is a complex and dynamic community, which plays a crucial role in tumor progression via the co-evolution of cancer cells and tumor stroma. Among them, tumor-associated macrophages (TAMs) and tumor neo-vessels are two key components in the tumor microenvironment during cancer invasion. In addition, programmed cell death ligand 1/programmed cell death ligand 1 (PD-1/PD-L1) also plays an important role in tumorigenesis and development, and the clinical strategies to block PD-1/PD-L1 pathway could have great benefits for cancer patients. This study was aimed at analyzing the quantitative expression and prognostic significance of TAMs, tumor neo-vessels and PD-L1 in tumor microenvironment and exploring the relations between the expression of above components with the patients' prognosis of non-small cell lung cancer (NSCLC).
Methods: Clinico-pathological data and surgical specimens of 92 patients with NSCLC were collected, and immunohistochemistry was used to stain the expression of TAMs, tumor neo-vessels and PD-L1 on tumor tissue and peri-tumor tissues. The inverted microscopy was used to take pictures and Image-pro Plus 6.0 software was used for quantitative analysis. The clinicopathological characteristics and overall survival (OS) were analyzed.
Results: The median OS of 92 NSCLC cases was 22.5 month. The expression of TAMs, tumor neo-vessels and PD-L1 in tumor tissue and peri-tumor tissues were not statistically significant (P>0.05). According to the cutoff of above key three components in tumor microenvironment, all the cases could be classified into high, middle and low expression groups. The survival analysis demonstrated that the OS in high expression group of TAMs (P=0.016) and PD-L1 (P=0.002) was shorter than the other two groups, respectively, with statistical significance. The OS in high tumor neo vessels group was shorter than the other two groups. However, there was no statistical significance between these three group (P=0.626). Combined with above the three components, all the cases could be classified into low, middle and high density groups. The survival analysis demonstrated that the median OS of combined high density group was shorter than the other two groups (P=0.001). Multivariate analysis by Cox regression indicated that pathological type, TAMs and PD-L1 expression were the independent prognostic factors.
Conclusions: The key components of TAMs and PD-L1 in tumor microenvironment are closely related to the prognosis of NSCLC patients.
【中文题目：微环境中巨噬细胞、肿瘤新生血管及PD-L1的表达及其与非小细胞肺癌患者预后的关系】 【中文摘要：背景与目的 肿瘤微环境是肿瘤细胞赖以生存的复杂环境。其中肿瘤相关巨噬细胞（tumor-associated macrophages, TAMs）、肿瘤新生血管及程序性死亡受体1/程序性死亡受体-配体1（programmed cell death protein 1/programmed cell death ligand 1, PD-1/PD-L1）作为关键部分，在肿瘤发生、发展过程中起重要作用，影响患者预后。本研究旨在阐明TAMs、肿瘤新生血管和PD-L1的表达与非小细胞肺癌（non-small cell lung cancer, NSCLC）临床病理特征的相关性，并探讨它们对NSCLC预后的影响。方法 收集92例NSCLC患者的临床病理资料及手术标本，采用免疫组化法检测癌组织和癌旁组织中TAMs、肿瘤新生血管和PD-L1的表达，采用配备有Olympus-DP72图像采集系统的Olympus-BX51正置显微镜进行拍照并用Image-pro Plus 6.0软件进行半定量分析。结果 癌组织与癌旁组织中TAMs、肿瘤新生血管和PD-L1的表达差异无统计学意义（P>0.05）。根据肿瘤微环境中各组分的定量表达，可将其分为低、中、高表达组。癌组织中TAMs的低、中和高密度组的中位总生存（overall survival, OS）分别是36个月（95%CI: 25.3-46.7）、26个月（95%CI: 12.2-39.8）和16个月（95%CI: 9.4-22.6），差异具有统计学意义（P=0.016）；肿瘤新生血管的低、中和高密度组的中位OS分别为30个月（95%CI: 22.5-37.5）、28个月（95%CI: 18.1-37.9）和25个月（95%CI: 14.6-35.4），差异无统计学意义（P=0.626）；PD-L1的低、中和高表达组的中位OS分别为35个月（95%CI: 29.4-40.6），28个月（95%CI: 13.6-42.4）和17个月（95%CI: 10.5-23.5），差异具有统计学意义（P=0.002）。联合低、中和高表达组的中位OS分别为36个月（95%CI: 30.6-41.4）、26个月（95%CI: 19.2-32.8）和9个月（95%CI: 4.4-13.6），差异具有统计学意义（P=0.001）。Cox回归分析结果显示，病理分型、TAMs和PD-L1均为肺癌患者的独立预后因素。结论 肿瘤微环境关键成分PD-L1及TAMs的表达与NSCLC患者的预后密切相关。】 【中文关键词：肺肿瘤；肿瘤微环境；肿瘤相关巨噬细胞; 程序性死亡受体-配体1；肿瘤新生血管】.
Keywords: Lung neoplasms; Programmed cell death ligand 1; Tumor microenvironment; Tumor neo-vessels; Tumor-associated macrophages.