Prognostic Significance of Plasma Neutrophil Extracellular Trap Levels in Patients with Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

• Published in: Biomedicines Vol. 12; no. 8; p. 1831
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.08.2024; MDPI
• Subjects: anti-PD-1 antibody; anti-PD-L1 antibody; Anticoagulants; Blood; Cancer therapies; Chemokines; Chemotherapy; Citrulline; Drug therapy; Extrachromosomal DNA; Gene expression; Health aspects; Histone H3; Histones; immune checkpoint inhibitor; Immune checkpoint inhibitors; Immunotherapy; Leukocytes (mononuclear); Leukocytes (neutrophilic); Ligands; Lung cancer; Lung cancer, Non-small cell; Measurement; Medical prognosis; Metastasis; Monoclonal antibodies; neutrophil extracellular trap (NET); Neutrophils; non-small cell lung cancer (NSCLC); Non-small cell lung carcinoma; Patient outcomes; Patients; PD-1 protein; PD-L1 protein; Peripheral blood mononuclear cells; Plasma; Plasma levels; Prognosis; Sample size; Small cell lung carcinoma; Statistical analysis; Tumor necrosis factor-TNF; Tumors; Japan; United States > US
• ISSN: 2227-9059; 2227-9059
• 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; p < 0.001, HR 1.702, 95% CI 1.356–2.137) and progression-free survival (PFS; p < 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 (p = 0.002) and PFS (p < 0.001). Additionally, high NET levels after treatment were also significantly associated with worse OS (p < 0.001) and PFS (p < 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.