Schernberg Antoine, Blanchard Pierre, Chargari Cyrus, Deutsch Eric
a Radiation Oncology Department , SIRIC SOCRATES, Gustave Roussy Cancer Campus , Villejuif , France.
b INSERM U1018, CESP , Université Paris-Sud, Université Paris-Saclay , Villejuif , France.
Acta Oncol. 2017 Nov;56(11):1522-1530. doi: 10.1080/0284186X.2017.1348623. Epub 2017 Aug 23.
Neutrophils are the most abundant blood-circulating white blood cells, continuously generated in the bone marrow. Growing evidence suggests they regulate the innate and adaptive immune system during tumor evolution. This review will first summarize the recent findings on neutrophils as a key player in cancer evolution, then as a potential biomarker, and finally as therapeutic targets, with respective focuses on the interplay with radiation therapy. A complex interplay: Neutrophils have been associated with tumor progression through multiple pathways. Ionizing radiation has cytotoxic effects on cancer cells, but the sensitivity to radiation therapy in vivo differ from isolated cancer cells in vitro, partially due to the tumor microenvironment. Different microenvironmental states, whether baseline or induced, can modulate or even attenuate the effects of radiation, with consequences for therapeutic efficacy. Inflammatory biomarkers: Inflammation-based scores have been widely studied as prognostic biomarkers in cancer patients. We have performed a large retrospective cohort of patients undergoing radiation therapy (1233 patients), with robust relationship between baseline blood neutrophil count and 3-year's patient's overall survival in patients with different cancer histologies. (Pearson's correlation test: p = .001, r = -.93). Therapeutic approaches: Neutrophil-targeting agents are being developed for the treatment of inflammatory and autoimmune diseases. Neutrophils either can exert antitumoral (N1 phenotype) or protumoral (N2 phenotype) activity, depending on the Tumor Micro Environment. Tumor associated N2 neutrophils are characterized by high expression of CXCR4, VEGF, and gelatinase B/MMP9. TGF-β within the tumor microenvironment induces a population of TAN with a protumor N2 phenotype. TGF-β blockade slows tumor growth through activation of CD8 + T cells, macrophages, and tumor associated neutrophils with an antitumor N1 phenotype.
This supports the need for prospective neutrophils evaluation in clinical trials, making neutrophils a predictive biomarker with potential specific therapies.
中性粒细胞是骨髓中持续产生的、循环血液中最丰富的白细胞。越来越多的证据表明，它们在肿瘤发生发展过程中调节先天性和适应性免疫系统。本综述首先总结中性粒细胞作为癌症发生发展关键参与者的最新研究发现，其次总结其作为潜在生物标志物的研究发现，最后总结其作为治疗靶点的研究发现，并分别重点关注与放射治疗的相互作用。复杂的相互作用：中性粒细胞通过多种途径与肿瘤进展相关。电离辐射对癌细胞具有细胞毒性作用，但体内对放射治疗的敏感性与体外分离的癌细胞不同，部分原因是肿瘤微环境。不同的微环境状态，无论是基线状态还是诱导状态，都可以调节甚至减弱辐射的作用，从而影响治疗效果。炎症生物标志物：基于炎症的评分作为癌症患者的预后生物标志物已得到广泛研究。我们对接受放射治疗的患者进行了一项大型回顾性队列研究（1233例患者），发现不同癌症组织学类型患者的基线血中性粒细胞计数与3年患者总生存率之间存在密切关系。（Pearson相关检验：p = 0.001，r = -0.93）。治疗方法：针对中性粒细胞的药物正在研发用于治疗炎症和自身免疫性疾病。中性粒细胞根据肿瘤微环境可发挥抗肿瘤（N1表型）或促肿瘤（N2表型）活性。肿瘤相关的N2中性粒细胞以CXCR4、VEGF和明胶酶B/MMP9的高表达为特征。肿瘤微环境中的转化生长因子-β（TGF-β）诱导一群具有促肿瘤N2表型的肿瘤相关中性粒细胞（TAN）。TGF-β阻断通过激活具有抗肿瘤N1表型的CD8 + T细胞、巨噬细胞和肿瘤相关中性粒细胞来减缓肿瘤生长。
这支持在临床试验中对中性粒细胞进行前瞻性评估的必要性，使中性粒细胞成为具有潜在特异性治疗方法的预测性生物标志物。
