Shaul Merav E, Levy Liran, Sun Jing, Mishalian Inbal, Singhal Sunil, Kapoor Veena, Horng Wenhwai, Fridlender Gil, Albelda Steven M, Fridlender Zvi G
Institute of Pulmonary Medicine, Hadassah-Hebrew University Medical Center , Jerusalem, Israel.
Thoracic Oncology Research Laboratory, University of Pennsylvania , Philadelphia, PA, USA.
Oncoimmunology. 2016 Sep 13;5(11):e1232221. doi: 10.1080/2162402X.2016.1232221. eCollection 2016.
It is becoming increasingly clear that tumor-associated neutrophils (TANs) play an important role in cancer biology, through direct impact on tumor growth and by recruitment of other cells types into the tumor. The function of neutrophils in cancer has been the subject of seemingly contradicting reports, pointing toward a dual role played by TANs in tumor progression. The existence of multiple neutrophil subsets, as well as phenotypic modulation of the neutrophils by various factors in the tumor microenvironment, has been shown. TGFβ plays a significant role in the determination of neutrophils' phenotype, by shifting the balance from an antitumor (N1) toward a more permissive (N2) phenotype. The full range of mechanisms responsible for the pro- vs. antitumor effects of TANs has not yet been elucidated. Therefore, the ability to identify the different neutrophil subpopulations in the tumor is critical in order to understand TANs evolution and contribution throughout tumor progression. Using a transcriptomic approach, we identified alternations in gene expression profile following TGFβ inhibition. We show that N1 and N2 TANs represent distinct subpopulations with different transcriptional signatures and both differ from naive bone marrow neutrophils. The analysis highlights a clear difference in pathways involved in neutrophil function such as cytoskeletal organization and antigen presentation, as well as alterations in chemokine profile, eventually affecting their effect on tumor cells and tumor growth. These data highlights several potential new pathways and mechanisms by which neutrophils can influence both the tumor cells and the adaptive immune system.
越来越明显的是，肿瘤相关中性粒细胞（TANs）在癌症生物学中发挥着重要作用，其通过直接影响肿瘤生长以及将其他细胞类型募集到肿瘤中来实现。中性粒细胞在癌症中的功能一直是看似相互矛盾的报道的主题，这表明TANs在肿瘤进展中发挥着双重作用。已经证实存在多种中性粒细胞亚群，以及肿瘤微环境中的各种因素对中性粒细胞的表型调节。转化生长因子β（TGFβ）通过将平衡从抗肿瘤（N1）表型转向更具耐受性的（N2）表型，在中性粒细胞表型的确定中发挥着重要作用。导致TANs产生促肿瘤与抗肿瘤作用的完整机制尚未阐明。因此，识别肿瘤中不同中性粒细胞亚群的能力对于理解TANs在整个肿瘤进展过程中的演变和贡献至关重要。我们采用转录组学方法，确定了TGFβ抑制后基因表达谱的变化。我们表明，N1和N2 TANs代表具有不同转录特征的不同亚群，且两者均与未成熟的骨髓中性粒细胞不同。该分析突出了中性粒细胞功能所涉及的途径（如细胞骨架组织和抗原呈递）的明显差异，以及趋化因子谱的变化，最终影响它们对肿瘤细胞和肿瘤生长的作用。这些数据突出了中性粒细胞影响肿瘤细胞和适应性免疫系统的几种潜在新途径和机制。
