Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors
Introduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-01-01
|
| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1324898/full |
| _version_ | 1797294774572548096 |
|---|---|
| author | Yoshiro Nakahara Yoshiro Nakahara Taku Kouro Taku Kouro Satoru Motoyama Satoru Motoyama Satoru Motoyama Masatomo Miura Kazuma Fujita Yuka Igarashi Naoko Higashijima Norikazu Matsuo Hidetomo Himuro Hidetomo Himuro Feifei Wei Feifei Wei Shun Horaguchi Shun Horaguchi Shun Horaguchi Kayoko Tsuji Kayoko Tsuji Yasunobu Mano Yasunobu Mano Mitsuru Komahashi Mitsuru Komahashi Mitsuru Komahashi Haruhiro Saito Koichi Azuma Tetsuro Sasada Tetsuro Sasada |
| author_facet | Yoshiro Nakahara Yoshiro Nakahara Taku Kouro Taku Kouro Satoru Motoyama Satoru Motoyama Satoru Motoyama Masatomo Miura Kazuma Fujita Yuka Igarashi Naoko Higashijima Norikazu Matsuo Hidetomo Himuro Hidetomo Himuro Feifei Wei Feifei Wei Shun Horaguchi Shun Horaguchi Shun Horaguchi Kayoko Tsuji Kayoko Tsuji Yasunobu Mano Yasunobu Mano Mitsuru Komahashi Mitsuru Komahashi Mitsuru Komahashi Haruhiro Saito Koichi Azuma Tetsuro Sasada Tetsuro Sasada |
| author_sort | Yoshiro Nakahara |
| collection | DOAJ |
| description | Introduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated.Methods: Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Plasma levels of IL-6, sIL-6R, sgp130, and their complexes were assessed by Cox regression hazard model to evaluate their clinical significance. The clinical role of IL-6 or IL-6R genetic polymorphisms was also analyzed.Results: Cox regression analysis showed that higher plasma IL-6 levels significantly predicted unfavorable overall survival (OS; hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.05–1.68, p = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance (p = 0.882 and p = 0.934, respectively). In addition, the estimated concentrations of binary IL-6:sIL-6R and ternary IL-6:sIL-6R:sgp130 complexes and their ratios (binary/ternary complex) were not significantly associated with OS (p = 0.647, p = 0.727, and p = 0.273, respectively). Furthermore, the genetic polymorphisms of IL-6 (−634G>C) and IL-6R (48892A>C) showed no clinical role by Kaplan-Meier survival analysis (p = 0.908 and p = 0.639, respectively).Discussion: These findings demonstrated the clinical significance of plasma levels of IL-6, but not of other IL-6 signaling components, sIL-6R and sgp130, suggesting that classical IL-6 signaling, but not trans-signaling, may be related to anti-tumor immune responses in cancer patients treated with ICIs. |
| first_indexed | 2024-03-07T21:36:57Z |
| format | Article |
| id | doaj.art-c99406045248454083cba711ad18ebf5 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-03-07T21:36:57Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-c99406045248454083cba711ad18ebf52024-02-26T12:33:20ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2024-01-011110.3389/fcell.2023.13248981324898Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitorsYoshiro Nakahara0Yoshiro Nakahara1Taku Kouro2Taku Kouro3Satoru Motoyama4Satoru Motoyama5Satoru Motoyama6Masatomo Miura7Kazuma Fujita8Yuka Igarashi9Naoko Higashijima10Norikazu Matsuo11Hidetomo Himuro12Hidetomo Himuro13Feifei Wei14Feifei Wei15Shun Horaguchi16Shun Horaguchi17Shun Horaguchi18Kayoko Tsuji19Kayoko Tsuji20Yasunobu Mano21Yasunobu Mano22Mitsuru Komahashi23Mitsuru Komahashi24Mitsuru Komahashi25Haruhiro Saito26Koichi Azuma27Tetsuro Sasada28Tetsuro Sasada29Department of Respiratory Medicine, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDepartment of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDivision of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa, JapanDepartment of Comprehensive Cancer Control, Akita University Graduate School of Medicine, Akita, JapanDivision of Esophageal Surgery, Akita University Hospital, Akita, JapanDepartment of Gastroenterological Surgery, Japanese Red Cross Akita Hospital, Akita, JapanDepartment of Pharmacy, Akita University Hospital, Akita, JapanDepartment of Pharmacy, Akita University Hospital, Akita, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDivision of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDivision of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDivision of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDivision of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa, Japan0Department of Pediatric Surgery, Nihon University School of Medicine, Tokyo, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDivision of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDivision of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDivision of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa, Japan0Department of Pediatric Surgery, Nihon University School of Medicine, Tokyo, JapanDepartment of Respiratory Medicine, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDivision of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, JapanCancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Kanagawa, JapanDivision of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa, JapanIntroduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated.Methods: Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Plasma levels of IL-6, sIL-6R, sgp130, and their complexes were assessed by Cox regression hazard model to evaluate their clinical significance. The clinical role of IL-6 or IL-6R genetic polymorphisms was also analyzed.Results: Cox regression analysis showed that higher plasma IL-6 levels significantly predicted unfavorable overall survival (OS; hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.05–1.68, p = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance (p = 0.882 and p = 0.934, respectively). In addition, the estimated concentrations of binary IL-6:sIL-6R and ternary IL-6:sIL-6R:sgp130 complexes and their ratios (binary/ternary complex) were not significantly associated with OS (p = 0.647, p = 0.727, and p = 0.273, respectively). Furthermore, the genetic polymorphisms of IL-6 (−634G>C) and IL-6R (48892A>C) showed no clinical role by Kaplan-Meier survival analysis (p = 0.908 and p = 0.639, respectively).Discussion: These findings demonstrated the clinical significance of plasma levels of IL-6, but not of other IL-6 signaling components, sIL-6R and sgp130, suggesting that classical IL-6 signaling, but not trans-signaling, may be related to anti-tumor immune responses in cancer patients treated with ICIs.https://www.frontiersin.org/articles/10.3389/fcell.2023.1324898/fullimmune checkpoint inhibitornon-small cell lung cancer (NSCLC)IL-6soluble IL-6 receptor (sIL-6R)soluble glycoprotein 130 (sgp130)PD-1 |
| spellingShingle | Yoshiro Nakahara Yoshiro Nakahara Taku Kouro Taku Kouro Satoru Motoyama Satoru Motoyama Satoru Motoyama Masatomo Miura Kazuma Fujita Yuka Igarashi Naoko Higashijima Norikazu Matsuo Hidetomo Himuro Hidetomo Himuro Feifei Wei Feifei Wei Shun Horaguchi Shun Horaguchi Shun Horaguchi Kayoko Tsuji Kayoko Tsuji Yasunobu Mano Yasunobu Mano Mitsuru Komahashi Mitsuru Komahashi Mitsuru Komahashi Haruhiro Saito Koichi Azuma Tetsuro Sasada Tetsuro Sasada Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors Frontiers in Cell and Developmental Biology immune checkpoint inhibitor non-small cell lung cancer (NSCLC) IL-6 soluble IL-6 receptor (sIL-6R) soluble glycoprotein 130 (sgp130) PD-1 |
| title | Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors |
| title_full | Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors |
| title_fullStr | Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors |
| title_full_unstemmed | Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors |
| title_short | Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors |
| title_sort | circulating il 6 and not its circulating signaling components sil 6r and sgp130 demonstrate clinical significance in nsclc patients treated with immune checkpoint inhibitors |
| topic | immune checkpoint inhibitor non-small cell lung cancer (NSCLC) IL-6 soluble IL-6 receptor (sIL-6R) soluble glycoprotein 130 (sgp130) PD-1 |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1324898/full |
| work_keys_str_mv | AT yoshironakahara circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT yoshironakahara circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT takukouro circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT takukouro circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT satorumotoyama circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT satorumotoyama circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT satorumotoyama circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT masatomomiura circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT kazumafujita circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT yukaigarashi circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT naokohigashijima circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT norikazumatsuo circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT hidetomohimuro circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT hidetomohimuro circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT feifeiwei circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT feifeiwei circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT shunhoraguchi circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT shunhoraguchi circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT shunhoraguchi circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT kayokotsuji circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT kayokotsuji circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT yasunobumano circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT yasunobumano circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT mitsurukomahashi circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT mitsurukomahashi circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT mitsurukomahashi circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT haruhirosaito circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT koichiazuma circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT tetsurosasada circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors AT tetsurosasada circulatingil6andnotitscirculatingsignalingcomponentssil6randsgp130demonstrateclinicalsignificanceinnsclcpatientstreatedwithimmunecheckpointinhibitors |