Lonardi Silvia, Missale Francesco, Calza Stefano, Bugatti Mattia, Vescovi Raffaella, Debora Bresciani, Uppaluri Ravindra, Egloff Ann Marie, Mattavelli Davide, Lombardi Davide, Benerini Gatta Luisa, Marini Olivia, Tamassia Nicola, Gardiman Elisa, Cassatella Marco A, Scapini Patrizia, Nicolai Piero, Vermi William
Section of Pathology Department of Molecular and Translational Medicine University of Brescia Brescia Italy.
ASST- Spedali Civili di Brescia Brescia Italy.
Clin Transl Immunology. 2021 Feb 16;10(2):e1252. doi: 10.1002/cti2.1252. eCollection 2021.
The role of tumor-associated neutrophils (TANs) in the nodal spread of cancer cells remains unexplored. The present study evaluates the occurrence and clinical significance of human nodal TANs.
The relevance, derivation, phenotype and interactions of nodal TANs were explored a large immunohistochemical analysis of carcinoma-draining lymph nodes, and their clinical significance was evaluated on a retrospective cohort of oral squamous cell carcinomas (OSCC). The tumor-promoting function of nodal TAN was probed in the OSCC TCGA dataset combining TAN and epithelial-to-mesenchymal transition (EMT) signatures.
The pan-carcinoma screening identified a consistent infiltration (59%) of CD66b TANs in tumor-draining lymph nodes (TDLNs). Microscopic findings, including the occurrence of intra-lymphatic conjugates of TANs and cancer cells, indicate that TANs migrate through lymphatic vessels. experiments revealed that OSCC cell lines sustain neutrophil viability and activation via release of GM-CSF. Moreover, by retrospective analysis, a high CD66b TAN density in M-TDLNs of OSCC ( = 182 patients) predicted a worse prognosis. The analysis of the OSCC-TCGA dataset unveiled that the expression of a set of neutrophil-specific genes in the primary tumor (PT) is highly associated with an EMT signature, which predicts nodal spread. Accordingly, in the PT of OSCC cases, CD66bTANs co-localised with PDPNS100A9 EMT-switched tumor cells in areas of lymphangiogenesis. The pro-EMT signature is lacking in peripheral blood neutrophils from OSCC patients, suggesting tissue skewing of TANs.
Our findings are consistent with a novel pro-tumoral TAN compartment that may promote nodal spread EMT, through the lymphatics.
肿瘤相关中性粒细胞（TANs）在癌细胞淋巴结转移中的作用尚不清楚。本研究评估人淋巴结TANs的发生情况及其临床意义。
通过对癌引流淋巴结进行大规模免疫组化分析，探讨淋巴结TANs的相关性、来源、表型及相互作用，并在口腔鳞状细胞癌（OSCC）回顾性队列中评估其临床意义。结合TAN和上皮-间质转化（EMT）特征，在OSCC TCGA数据集中探究淋巴结TAN的促肿瘤功能。
全癌筛查发现肿瘤引流淋巴结（TDLNs）中CD66b⁺ TANs存在一致的浸润（59%）。包括TANs与癌细胞的淋巴内结合物出现等微观发现表明，TANs通过淋巴管迁移。实验显示，OSCC细胞系通过释放GM-CSF维持中性粒细胞的活力和激活。此外，通过回顾性分析，OSCC（n = 182例患者）转移瘤引流淋巴结（M-TDLNs）中高CD66b⁺ TAN密度预示预后较差。对OSCC-TCGA数据集的分析表明，原发性肿瘤（PT）中一组中性粒细胞特异性基因的表达与预测淋巴结转移的EMT特征高度相关。因此，在OSCC病例的PT中，CD66b⁺ TANs在淋巴管生成区域与PDPN⁺ S100A9 EMT转换的肿瘤细胞共定位。OSCC患者外周血中性粒细胞缺乏促EMT特征，提示TANs存在组织偏向性。
我们的研究结果与一个新的促肿瘤TAN区室一致，该区域可能通过淋巴管促进淋巴结转移和EMT。
