Horaguchi Shun, Nakahara Yoshiro, Igarashi Yuka, Kouro Taku, Wei Feifei, Murotani Kenta, Udagawa Seiichi, Higashijima Naoko, Matsuo Norikazu, Murakami Shuji, Kato Terufumi, Kondo Tetsuro, Xiang Huihui, Kasajima Rika, Himuro Hidetomo, Tsuji Kayoko, Mano Yasunobu, Komahashi Mitsuru, Miyagi Yohei, Saito Haruhiro, Azuma Koichi, Uehara Shuichiro, Sasada Tetsuro
Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan.
Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan.
Biomedicines. 2024 Aug 12;12(8):1831. doi: 10.3390/biomedicines12081831.
Neutrophil extracellular traps (NETs) released from neutrophils are related to cancer progression. However, the relationship between the therapeutic effects of immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-PD-L1 antibodies and plasma NET concentration in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, concentrations of citrullinated histone H3 (CitH3), a surrogate marker of NETs, in plasma before/after treatment were examined in patients with advanced or recurrent NSCLC undergoing ICI treatment (n = 185). The clinical significances of NET levels before/after treatment and posttreatment changes were statistically evaluated. As a result, multivariate Cox analysis showed that high NET levels before treatment were statistically significant predictors of unfavorable overall survival (OS; < 0.001, HR 1.702, 95% CI 1.356-2.137) and progression-free survival (PFS; < 0.001, HR 1.566, 95% CI 1.323-1.855). The Kaplan-Meier curves showed significant separation between the high- and low-NET groups in OS ( = 0.002) and PFS ( < 0.001). Additionally, high NET levels after treatment were also significantly associated with worse OS ( < 0.001) and PFS ( < 0.001) by multivariate Cox analysis. Notably, the pretreatment NET levels were significantly correlated with the plasma levels of NET-related inflammatory cytokines, such as IL-6 and IL-8, and with NET-related gene expression and immune-suppressive profile in peripheral blood mononuclear cells. Our findings suggest that NETs released from activated neutrophils might reduce the clinical efficacy of ICIs in patients with NSCLC.
中性粒细胞释放的中性粒细胞胞外陷阱（NETs）与癌症进展相关。然而，抗PD-1和抗PD-L1抗体等免疫检查点抑制剂（ICIs）的治疗效果与非小细胞肺癌（NSCLC）患者血浆NET浓度之间的关系尚不清楚。在本研究中，对185例接受ICI治疗的晚期或复发性NSCLC患者治疗前后血浆中NETs的替代标志物瓜氨酸化组蛋白H3（CitH3）的浓度进行了检测。对治疗前后NET水平及治疗后变化的临床意义进行了统计学评估。结果，多因素Cox分析显示，治疗前高NET水平是总生存期（OS；P<0.001，HR 1.702，95%CI 1.356-2.137）和无进展生存期（PFS；P<0.001，HR 1.566，95%CI 1.323-1.855）不佳的统计学显著预测因素。Kaplan-Meier曲线显示，高NET组和低NET组在OS（P=0.002）和PFS（P<0.001）方面有显著差异。此外，多因素Cox分析显示，治疗后高NET水平也与较差的OS（P<0.001）和PFS（P<0.001）显著相关。值得注意的是，治疗前NET水平与NET相关炎性细胞因子如IL-6和IL-8的血浆水平、外周血单个核细胞中NET相关基因表达及免疫抑制谱显著相关。我们的研究结果表明，活化的中性粒细胞释放的NETs可能会降低ICIs对NSCLC患者的临床疗效。
