肿瘤细胞治疗研究
英文原题：TGF-β1 drives neutrophil extracellular traps formation to promote CD8(+) T cell exhaustion via the ERK-c-Fos-JunB axis, mediating gastric cancer immunotherapy resistance.
TGF-β1驱动CD177+中性粒细胞释放NETs，NETs通过ERK-c-Fos-JunB通路诱导CD8+T细胞耗竭，从而介导GC对抗PD-1治疗的耐药性。此外，靶向NETs形成并将trametinib与PD-1抑制剂联合使用可显著逆转CD8+T细胞耗竭，发挥协同抗肿瘤作用，为克服GC抗PD-1治疗耐药提供潜在治疗策略。
胃癌（GC）对抗程序性细胞死亡蛋白-1（PD-1）治疗的耐药与免疫抑制性肿瘤微环境密切相关。然而，中性粒细胞在抗PD-1治疗耐药中的作用仍不清楚。
对接受抗PD-1治疗的晚期GC患者的肿瘤样本进行了单细胞RNA测序，以鉴定与中性粒细胞胞外诱捕网（NETs）相关的中性粒细胞亚群。通过多组学分析、流式细胞术、多重免疫荧光和体外共培养进行了多层面实验验证。在YTN16肿瘤小鼠模型中评估了靶向NETs和CD8 + T细胞耗竭的治疗策略。
我们鉴定出一个与NETs相关的中性粒细胞亚群，该亚群在对抗PD-1治疗耐药的GC患者中富集。该亚群以CD177为标志，并表现出高度的NETs释放潜能。GC患者外周血NETs水平和CD177+中性粒细胞比例可作为评估PD-1抑制剂疗效的标志物。此外，在GC中高表达并与CD177+中性粒细胞空间共定位的转化生长因子-β1（TGF-β1），可能通过Smad3-NFE2轴诱导中性粒细胞释放NETs。NETs通过激活MEK/ERK-c-Fos/JunB轴促进CD8+ T细胞耗竭，表现为PD-1/TIM3表达增加以及干扰素-γ/肿瘤坏死因子-α分泌减少。体内实验证实，使用DNase I或TGF-β1抑制剂靶向抑制NETs形成可显著抑制肿瘤生长和CD8+ T细胞耗竭。值得注意的是，MEK抑制剂trametinib逆转了与CD8+ T细胞耗竭相关的免疫抑制微环境，并与抗PD-1治疗协同增强抗肿瘤疗效。
BACKGROUND: Resistance to anti-programmed cell death protein-1 (PD-1) treatment in gastric cancer (GC) is closely associated with an immunosuppressive tumor microenvironment. However, the role of neutrophils in resistance to anti-PD-1 therapy remains unclear. METHODS: Single-cell RNA sequencing was performed on tumor samples from patients with advanced GC receiving anti-PD-1 therapy to identify neutrophil subsets associated with neutrophil extracellular traps (NETs). Multilevel experimental validation was conducted using multiomics analysis, flow cytometry, multiplex immunofluorescence, and in vitro co-culture. Therapeutic strategies targeting NETs and CD8 + T-cell exhaustion were evaluated in a mouse model of YTN16 tumors. RESULTS: We identified a NETs-associated neutrophil subset enriched in patients with GC resistant to anti-PD-1 treatment. This subset was marked by CD177, and it exhibited a high potential for NETs release. Peripheral blood NETs levels and CD177 + neutrophil ratios in patients with GC act as markers for evaluating the efficacy of PD-1 inhibitors. Furthermore, transforming growth factor-β1 (TGF-β1), which was highly expressed in GC and spatially colocalized with CD177 + neutrophils, might induce neutrophils to release NETs via the Smad3-NFE2 axis. NETs promoted CD8 + T cell exhaustion by activating the MEK/ERK-c-Fos/JunB axis, as evidenced by increased PD-1/TIM3 expression and reduced interferon-gamma/tumor necrosis factor-alpha secretion. In vivo experiments confirmed that targeted inhibition of NETs formation using DNase I or TGF-β1 inhibitors significantly suppressed tumor growth and CD8 + T cell exhaustion. Notably, the MEK inhibitor trametinib reversed the immunosuppressive microenvironment associated with CD8 + T cell exhaustion and synergistically enhanced the antitumor efficacy with anti-PD-1 therapy. CONCLUSIONS: TGF-β1 drives CD177 + neutrophils to release NETs, which induce CD8 + T cell exhaustion via the ERK-c-Fos-JunB pathway, thereby mediating resistance to anti-PD-1 treatment in GC. Furthermore, targeting NETs formation and combining trametinib with PD-1 inhibitors can significantly reverse CD8 + T cell exhaustion, exert synergistic antitumor effects, and offer a potential therapeutic strategy for overcoming resistance to anti-PD-1 therapy in GC.
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