Prognostic Significance of Plasma Neutrophil Extracellular Trap Levels in Patients with Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors
Shun Horaguchi,
Yoshiro Nakahara,
Yuka Igarashi,
Taku Kouro,
Feifei Wei,
Kenta Murotani,
Seiichi Udagawa,
Naoko Higashijima,
Norikazu Matsuo,
Shuji Murakami,
Terufumi Kato,
Tetsuro Kondo,
Huihui Xiang,
Rika Kasajima,
Hidetomo Himuro,
Kayoko Tsuji,
Yasunobu Mano,
Mitsuru Komahashi,
Yohei Miyagi,
Haruhiro Saito,
Koichi Azuma,
Shuichiro Uehara,
Tetsuro Sasada
Affiliations
Shun Horaguchi
Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Yoshiro Nakahara
Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama 241-8515, Japan
Yuka Igarashi
Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Taku Kouro
Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Feifei Wei
Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Kenta Murotani
Biostatistics Center, Kurume University School of Medicine, Kurume 830-0011, Japan
Seiichi Udagawa
Mathematics Section, Division of Natural Sciences, Nihon University School of Medicine, Tokyo 173-0032, Japan
Naoko Higashijima
Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Norikazu Matsuo
Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
Shuji Murakami
Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama 241-8515, Japan
Terufumi Kato
Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama 241-8515, Japan
Tetsuro Kondo
Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama 241-8515, Japan
Huihui Xiang
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Rika Kasajima
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Hidetomo Himuro
Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Kayoko Tsuji
Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Yasunobu Mano
Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Mitsuru Komahashi
Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Yohei Miyagi
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
Haruhiro Saito
Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama 241-8515, Japan
Koichi Azuma
Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
Shuichiro Uehara
Department of Pediatric Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan
Tetsuro Sasada
Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama 241-8515, Japan
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 p p = 0.002) and PFS (p p 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.
