Neutrophils in the tumor microenvironment (TME) are heterogeneous populations associated with cancer prognosis and immunotherapy. However, the plasticity and function of heterogeneous neutrophils in the TME of non-small-cell lung cancer (NSCLC) remain unclear. Here, we show that neutrophils produce high levels of interleukin (IL)-8, which induce the differentiation of CD74^highSiglecF^low neutrophils and suppress the generation of CD74^lowSiglecF^high neutrophils in the TME of IL-8-humanized NSCLC mice. The CD74^highSiglecF^low neutrophils boost anti-tumor T cell responses via antigen cross-presentation. Deleting CD74 in IL-8-humanized neutrophils impairs T cell activation and exacerbates NSCLC progression, whereas a CD74 agonist enhances T cell activation and the efficacy of anti-programmed cell death 1 (PD-1) or osimertinib therapies. Additionally, the CD74^highCD63^low neutrophils in the TME and peripheral blood of advanced NSCLC patients phenocopy the CD74^highSiglecF^low neutrophils in the TME of NSCLC mice and correlate well with the responsiveness to anti-PD-1 plus chemotherapies. These findings demonstrate an IL-8-CD74^high neutrophil axis that promotes anti-tumor immunity in NSCLC.

中文翻译：

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中性粒细胞亚群激活抗肿瘤免疫并抑制非小细胞肺癌进展


肿瘤微环境 （TME） 中的中性粒细胞是与癌症预后和免疫治疗相关的异质性群体。然而，非小细胞肺癌 （NSCLC） TME 中异质性中性粒细胞的可塑性和功能仍不清楚。在这里，我们表明中性粒细胞产生高水平的白细胞介素 （IL）-8，诱导 CD74^高SiglecF^低中性粒细胞的分化，并抑制 CD74^低SiglecF^高中性粒细胞在 IL-8 人源化 NSCLC 小鼠的 TME 中产生。CD74^高SiglecF^低中性粒细胞通过抗原交叉呈递促进抗肿瘤 T 细胞反应。删除 IL-8 人源化中性粒细胞中的 CD74 会损害 T 细胞活化并加剧 NSCLC 进展，而 CD74 激动剂可增强 T 细胞活化和抗程序性细胞死亡 1 （PD-1） 或奥希替尼疗法的疗效。此外，晚期 NSCLC 患者 TME 和外周血中的 CD74^高CD63^低中性粒细胞表型复制 NSCLC 小鼠 TME 中的 CD74^高SiglecF^低中性粒细胞，并与对抗 PD-1 加化疗的反应性密切相关。这些发现表明 IL-8-CD74^高中性粒细胞轴可促进 NSCLC 的抗肿瘤免疫。