Background: Tumor-promoting inflammation and immune evasion are hallmarks of cancer, contributing to the survival and proliferation of tumor cells. Infiltrating leukocytes and pro-inflammatory cytokines released into the tumor microenvironment (TME) often cause this inflammation and immune evasion. Neutrophils are leukocytes that contribute to inflammation and have immunomodulatory functions. They are shown to have pro- or anti-tumorigenic roles contingent on cancer type.Methods: In this study, we examined the role of neutrophil recruitment in pancreatic cancer (PC) progression using patient samples and murine models.Results: We observed enhanced neutrophil infiltration and neutrophil extracellular trap (NET) formation, which were dependent on disease stage and tumor site. Our murine model studies showed that the infiltration of neutrophils and NETs was dependent on disease progression. Moreover, chemokine receptor CXCR2 and its ligands played a crucial role in neutrophil recruitment. The expression of CXCR2 and its ligands was associated with a worse prognosis for patients.Conclusions: Our data demonstrates that gemcitabine therapy enhances neutrophil recruitment and NET formation in PC. In addition, we observed altered neutrophil phenotypes in PC dependent on disease progression, suggesting a context-dependent immunomodulatory role. Together, our data demonstrate that CXCR2-driven neutrophil recruitment increases with PC progression, is enhanced by gemcitabine chemotherapy, promotes an immunosuppressive microenvironment, and is associated with poor patient survival.
背景：促肿瘤炎症与免疫逃逸是癌症的标志性特征，共同促进肿瘤细胞的存活与增殖。浸润至肿瘤微环境的白细胞及其释放的促炎细胞因子常引发此类炎症与免疫逃逸现象。中性粒细胞作为参与炎症反应并具有免疫调节功能的白细胞，其促癌或抑癌作用因癌症类型而异。 方法：本研究通过分析患者样本及小鼠模型，探讨中性粒细胞募集在胰腺癌进展中的作用机制。 结果：研究发现中性粒细胞浸润及中性粒细胞胞外诱捕网形成随疾病分期和肿瘤部位显著增强。小鼠模型实验证实中性粒细胞及NETs的浸润程度与疾病进展密切相关。趋化因子受体CXCR2及其配体在中性粒细胞募集过程中发挥关键作用，其表达水平与患者不良预后显著相关。 结论：研究数据表明吉西他滨治疗会增强胰腺癌中的中性粒细胞募集及NETs形成。同时发现中性粒细胞表型随疾病进展发生动态改变，提示其免疫调节功能具有情境依赖性。综合结果表明，CXCR2驱动的中性粒细胞募集随胰腺癌进展而增强，经吉西他滨化疗后进一步加剧，这种变化促进免疫抑制微环境形成，并与患者生存率降低密切相关。
Neutrophil Dynamics Contribute to Disease Progression and Poor Survival in Pancreatic Cancer
肿瘤(癌症)患者之家