Department of Thoracic Oncology and Surgery, China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Nanshan School, Guangzhou Medical University, Guangzhou, China.
Front Immunol. 2021 Nov 4;12:750046. doi: 10.3389/fimmu.2021.750046. eCollection 2021.
This study attempted to profile the tumor immune microenvironment (TIME) of non-small cell lung cancer (NSCLC) by multiplex immunofluorescence of 681 NSCLC cases. The number, density, and proportion of 26 types of immune cells in tumor nest and tumor stroma were evaluated, revealing some close interactions particularly between intrastromal neutrophils and intratumoral regulatory T cells (Treg) ( = 0.439, < 0.001), intrastromal CD4+CD38+ T cells and CD20-positive B cells ( = 0.539, < 0.001), and intratumoral CD8-positive T cells and M2 macrophages expressing PD-L1 ( = 0.339, < 0.001). Three immune subtypes correlated with distinct immune characteristics were identified using the unsupervised consensus clustering approach. The immune-activated subtype had the longest disease-free survival (DFS) and demonstrated the highest infiltration of CD4-positive T cells, CD8-positive T cells, and CD20-positive B cells. The immune-defected subtype was rich in cancer stem cells and macrophages, and these patients had the worst prognosis. The immune-exempted subtype had the highest levels of neutrophils and Tregs. Intratumoral CD68-positive macrophages, M1 macrophages, and intrastromal CD4+ cells, CD4+FOXP3- cells, CD8+ cells, and PD-L1+ cells were further found to be the most robust prognostic biomarkers for DFS, which were used to construct and validate the immune-related risk score for risk stratification (high . median . low) and the prediction of 5-year DFS rates (23.2% . 37.9% . 43.1%, < 0.001). In conclusion, the intricate and intrinsic structure of TIME in NSCLC was demonstrated, showing potency in subtyping and prognostication.
本研究通过对 681 例非小细胞肺癌（NSCLC）病例的多色免疫荧光分析，试图描绘 NSCLC 的肿瘤免疫微环境（TIME）。评估了肿瘤巢和肿瘤基质中 26 种免疫细胞的数量、密度和比例，揭示了一些密切的相互作用，特别是基质内中性粒细胞与肿瘤内调节性 T 细胞（Treg）之间（=0.439，<0.001）、基质内 CD4+CD38+T 细胞与 CD20 阳性 B 细胞之间（=0.539，<0.001）以及肿瘤内 CD8+阳性 T 细胞与表达 PD-L1 的 M2 巨噬细胞之间（=0.339，<0.001）。使用无监督共识聚类方法确定了与不同免疫特征相关的三种免疫亚型。免疫激活亚型的无病生存（DFS）最长，表现为 CD4+T 细胞、CD8+T 细胞和 CD20 阳性 B 细胞的浸润率最高。免疫缺陷亚型富含癌症干细胞和巨噬细胞，患者预后最差。免疫豁免亚型具有最高水平的中性粒细胞和 Treg。肿瘤内 CD68 阳性巨噬细胞、M1 巨噬细胞以及基质内 CD4+细胞、CD4+FOXP3-细胞、CD8+细胞和 PD-L1+细胞被进一步发现是 DFS 最稳健的预后生物标志物，用于构建和验证免疫相关风险评分，以进行风险分层（高、中、低）和预测 5 年 DFS 率（23.2%、37.9%、43.1%，<0.001）。总之，本研究显示 NSCLC 的 TIME 具有复杂而内在的结构，在亚分型和预后方面具有潜力。
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