Liu Qian, Qiao Meng, Lohinai Zoltan, Mao Shiqi, Pan Yingying, Wang Yan, Yang Shuo, Zhou Fei, Jiang Tao, Yi Xianghua, Ren Shengxiang, Zhou Caicun, Hirsch Fred R
Department of Medical Oncology, Shanghai Pulmonary Hospital and Lung Cancer Institute, Tongji University School of Medicine, Shanghai, China; Department of Oncology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, China.
Department of Medical Oncology, Shanghai Pulmonary Hospital and Lung Cancer Institute, Tongji University School of Medicine, Shanghai, China.
Lung Cancer. 2021 Dec;162:194-202. doi: 10.1016/j.lungcan.2021.11.003. Epub 2021 Nov 11.
Small cell lung cancer (SCLC) is a systemic disease and most patients have metastases at diagnosis. Better understanding of the underlying mechanisms of SCLC metastasis may provide potential approach to improve clinical outcome.
HTG Edge-seq was used to identify the differential gene expression between primary SCLC lesions and paired metastatic lymph nodes (LN). Overall survival (OS) analysis was performed in patients with different levels of plasma CCL19 concentration. Invasion, migration, proliferation, apoptosis and angiogenesis ability of SCLC cells and function of CD8 + T cells were evaluated in vitro to investigate the mechanism of CCL19 in promoting metastasis.
Four chemokines (CCL19, CCL21, CCL8, CCR1) were the most differentially expressed between primary lesions and metastatic LN. CCL19 was further investigated because its mRNA and protein level expression were also validated in four SCLC cell lines (H446, H69, H82, H196). Higher plasma CCL19 was associated with late lymph node (N3) metastasis (training cohort P = 0.044, validation cohort P = 0.020) and shorter OS (training cohort P = 0.040, validation cohort P = 0.047) in SCLC patients. Silencing CCL19 inhibited SCLC cell migration, invasion, proliferation and HUVECs tube formation. Furthermore, we found that CCL19 could decrease percentage of CD8 + Ki67 + and CD8 + GZMB + T cells and increase proportion of CD8 + PD1 + T cells.
CCL19 was associated with LN metastasis and poor prognosis in patients with SCLC. Its expression promoted tumor progression and metastasis and impaired the function of CD8 + T cells, suggesting CCL19 might be a potential target for SCLC.
小细胞肺癌（SCLC）是一种全身性疾病，大多数患者在诊断时已有转移。更好地了解SCLC转移的潜在机制可能为改善临床结局提供潜在方法。
采用HTG Edge-seq技术鉴定原发性SCLC病灶与配对转移淋巴结（LN）之间的差异基因表达。对血浆CCL19浓度不同水平的患者进行总生存期（OS）分析。在体外评估SCLC细胞的侵袭、迁移、增殖、凋亡和血管生成能力以及CD8 + T细胞的功能，以研究CCL19促进转移的机制。
四种趋化因子（CCL19、CCL21、CCL8、CCR1）在原发性病灶与转移LN之间差异表达最为显著。对CCL19进行了进一步研究，因为其mRNA和蛋白水平表达在四种SCLC细胞系（H446、H69、H82、H196）中也得到了验证。SCLC患者血浆CCL19水平较高与晚期淋巴结（N3）转移相关（训练队列P = 0.044，验证队列P = 0.020），且总生存期较短（训练队列P = 0.040，验证队列P = 0.047）。沉默CCL19可抑制SCLC细胞迁移、侵袭、增殖以及人脐静脉内皮细胞（HUVECs）管腔形成。此外，我们发现CCL19可降低CD8 + Ki67 +和CD8 + GZMB + T细胞的百分比，并增加CD8 + PD1 + T细胞的比例。
CCL19与SCLC患者的LN转移及不良预后相关。其表达促进肿瘤进展和转移，并损害CD8 + T细胞功能，提示CCL19可能是SCLC的一个潜在靶点。
