固体肿瘤放射治疗对中性粒细胞浸润及功能的影响：系统综述
The Effect of Radiation Treatment of Solid Tumors on Neutrophil Infiltration and Function: A Systematic Review
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影响因子:6.5
分区:医学1区 Top / 肿瘤学2区 核医学2区
发表日期:2024 Nov 01
作者:
Léon Raymakers, Thijs J Demmers, Gert J Meijer, I Quintus Molenaar, Hjalmar C van Santvoort, Martijn P W Intven, Jeanette H W Leusen, Patricia A Olofsen, Lois A Daamen
DOI:
10.1016/j.ijrobp.2024.07.2141
摘要
放射治疗（RT）能引发局部和系统性免疫反应，促进抗肿瘤免疫并提高免疫治疗的疗效。中性粒细胞是RT后最早浸润肿瘤的免疫细胞之一，被认为在初期抗肿瘤免疫反应中起关键作用。然而，肿瘤中的中性粒细胞与预后不良相关，RT引起的中性粒细胞浸润也可能改变肿瘤微环境（TME）的组成，促进肿瘤进展。为了改善肿瘤患者的RT疗效，理解RT与中性粒细胞之间的相互作用极为重要。本文回顾了有关RT影响实体瘤TME中中性粒细胞浸润和功能的文献，包括患者研究及动物模型研究。总体上，研究发现RT后，中性粒细胞水平升高，且在数日内达到峰值，最多可持续3周。大多数研究报道RT后中性粒细胞在TME中具有免疫抑制作用，表现为中性粒细胞色氨酶酶（indoleamine 2,3-dioxygenase 1, IDO1）和精氨酸酶（arginase 1）的表达上调，以及中性粒细胞胞外陷阱（NETs）的形成。RT还伴随中性粒细胞反应性氧种（ROS）生成增加，既可能增强抗肿瘤免疫，也可能抑制免疫反应。此外，多项动物模型显示通过耗竭中性粒细胞可以改善RT疗效，提示RT后中性粒细胞具有促肿瘤表型。我们认为，在制定RT策略时不应忽视中性粒细胞的作用，仍需在不同肿瘤类型中深入研究。另外，中性粒细胞或可作为靶点，通过结合RT与中性粒细胞靶向治疗，增强RT的抗肿瘤效果。
Abstract
Radiation therapy (RT) initiates a local and systemic immune response which can induce antitumor immunity and improve immunotherapy efficacy. Neutrophils are among the first immune cells that infiltrate tumors after RT and are suggested to be essential for the initial antitumor immune response. However, neutrophils in tumors are associated with poor outcomes and RT-induced neutrophil infiltration could also change the composition of the tumor microenvironment (TME) in favor of tumor progression. To improve RT efficacy for patients with cancer it is important to understand the interplay between RT and neutrophils. Here, we review the literature on how RT affects the infiltration and function of neutrophils in the TME of solid tumors, using both patients studies and preclinical murine in vivo models. In general, it was found that neutrophil levels increase and reach maximal levels in the first days after RT and can remain elevated up to 3 weeks. Most studies report an immunosuppressive role of neutrophils in the TME after RT, caused by upregulated expression of neutrophil indoleamine 2,3-dioxygenase 1 and arginase 1, as well as neutrophil extracellular trap formation. RT was also associated with increased reactive oxygen species production by neutrophils, which can both improve and inhibit antitumor immunity. In addition, multiple murine models showed improved RT efficacy when depleting neutrophils, suggesting that neutrophils have a protumor phenotype after RT. We conclude that the role of neutrophils should not be overlooked when developing RT strategies and requires further investigation in specific tumor types. In addition, neutrophils can possibly be exploited to enhance RT efficacy by combining RT with neutrophil-targeting therapies.