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Cross-cohort analysis identified an immune checkpoint-based signature to predict the clinical outcomes of neuroblastoma
BACKGROUND: Neuroblastoma (NB) places a substantial health burden on families worldwide. This study aimed to develop an immune checkpoint-based signature (ICS) based on the expression of immune checkpoints to better assess patient survival risk and potentially guide patient selection for immunothera...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10163522/ https://www.ncbi.nlm.nih.gov/pubmed/37130627 http://dx.doi.org/10.1136/jitc-2022-005980 |
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author | Zeng, Liang Xu, Hui Li, Shu-Hua Xu, Shuo-Yu Chen, Kai Qin, Liang-Jun Miao, Lei Wang, Fang Deng, Ling Wang, Feng-Hua Li, Le Fu, Sha Liu, Na Wang, Ran Li, Ying-Qing Wang, Hai-Yun |
author_facet | Zeng, Liang Xu, Hui Li, Shu-Hua Xu, Shuo-Yu Chen, Kai Qin, Liang-Jun Miao, Lei Wang, Fang Deng, Ling Wang, Feng-Hua Li, Le Fu, Sha Liu, Na Wang, Ran Li, Ying-Qing Wang, Hai-Yun |
author_sort | Zeng, Liang |
collection | PubMed |
description | BACKGROUND: Neuroblastoma (NB) places a substantial health burden on families worldwide. This study aimed to develop an immune checkpoint-based signature (ICS) based on the expression of immune checkpoints to better assess patient survival risk and potentially guide patient selection for immunotherapy of NB. METHODS: Immunohistochemistry integrated with digital pathology was used to determine the expression levels of 9 immune checkpoints in 212 tumor tissues used as the discovery set. The GSE85047 dataset (n=272) was used as a validation set in this study. In the discovery set, the ICS was constructed using a random forest algorithm and confirmed in the validation set to predict overall survival (OS) and event-free survival (EFS). Kaplan-Meier curves with a log-rank test were drawn to compare the survival differences. A receiver operating characteristic (ROC) curve was applied to calculate the area under the curve (AUC). RESULTS: Seven immune checkpoints, including PD-L1, B7-H3, IDO1, VISTA, T-cell immunoglobulin and mucin domain containing-3 (TIM-3), inducible costimulatory molecule (ICOS) and costimulatory molecule 40 (OX40), were identified as abnormally expressed in NB in the discovery set. OX40, B7-H3, ICOS and TIM-3 were eventually selected for the ICS model in the discovery set, and 89 patients with high risk had an inferior OS (HR 15.91, 95% CI 8.87 to 28.55, p<0.001) and EFS (HR 4.30, 95% CI 2.80 to 6.62, p<0.001). Furthermore, the prognostic value of the ICS was confirmed in the validation set (p<0.001). Multivariate Cox regression analysis demonstrated that age and the ICS were independent risk factors for OS in the discovery set (HR 6.17, 95% CI 1.78 to 21.29 and HR 1.18, 95% CI 1.12 to 1.25, respectively). Furthermore, nomogram A combining the ICS and age demonstrated significantly better prognostic value than age alone in predicting the patients’ 1-year, 3-year and 5-year OS in the discovery set (1 year: AUC, 0.891 (95% CI 0.797 to 0.985) vs 0.675 (95% CI 0.592 to 0.758); 3 years: 0.875 (95% CI 0.817 to 0.933) vs 0.701 (95% CI 0.645 to 0.758); 5 years: 0.898 (95% CI 0.851 to 0.940) vs 0.724 (95% CI 0.673 to 0.775), respectively), which was confirmed in the validation set. CONCLUSIONS: We propose an ICS that significantly differentiates between low-risk and high-risk patients, which might add prognostic value to age and provide clues for immunotherapy in NB. |
format | Online Article Text |
id | pubmed-10163522 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-101635222023-05-07 Cross-cohort analysis identified an immune checkpoint-based signature to predict the clinical outcomes of neuroblastoma Zeng, Liang Xu, Hui Li, Shu-Hua Xu, Shuo-Yu Chen, Kai Qin, Liang-Jun Miao, Lei Wang, Fang Deng, Ling Wang, Feng-Hua Li, Le Fu, Sha Liu, Na Wang, Ran Li, Ying-Qing Wang, Hai-Yun J Immunother Cancer Immunotherapy Biomarkers BACKGROUND: Neuroblastoma (NB) places a substantial health burden on families worldwide. This study aimed to develop an immune checkpoint-based signature (ICS) based on the expression of immune checkpoints to better assess patient survival risk and potentially guide patient selection for immunotherapy of NB. METHODS: Immunohistochemistry integrated with digital pathology was used to determine the expression levels of 9 immune checkpoints in 212 tumor tissues used as the discovery set. The GSE85047 dataset (n=272) was used as a validation set in this study. In the discovery set, the ICS was constructed using a random forest algorithm and confirmed in the validation set to predict overall survival (OS) and event-free survival (EFS). Kaplan-Meier curves with a log-rank test were drawn to compare the survival differences. A receiver operating characteristic (ROC) curve was applied to calculate the area under the curve (AUC). RESULTS: Seven immune checkpoints, including PD-L1, B7-H3, IDO1, VISTA, T-cell immunoglobulin and mucin domain containing-3 (TIM-3), inducible costimulatory molecule (ICOS) and costimulatory molecule 40 (OX40), were identified as abnormally expressed in NB in the discovery set. OX40, B7-H3, ICOS and TIM-3 were eventually selected for the ICS model in the discovery set, and 89 patients with high risk had an inferior OS (HR 15.91, 95% CI 8.87 to 28.55, p<0.001) and EFS (HR 4.30, 95% CI 2.80 to 6.62, p<0.001). Furthermore, the prognostic value of the ICS was confirmed in the validation set (p<0.001). Multivariate Cox regression analysis demonstrated that age and the ICS were independent risk factors for OS in the discovery set (HR 6.17, 95% CI 1.78 to 21.29 and HR 1.18, 95% CI 1.12 to 1.25, respectively). Furthermore, nomogram A combining the ICS and age demonstrated significantly better prognostic value than age alone in predicting the patients’ 1-year, 3-year and 5-year OS in the discovery set (1 year: AUC, 0.891 (95% CI 0.797 to 0.985) vs 0.675 (95% CI 0.592 to 0.758); 3 years: 0.875 (95% CI 0.817 to 0.933) vs 0.701 (95% CI 0.645 to 0.758); 5 years: 0.898 (95% CI 0.851 to 0.940) vs 0.724 (95% CI 0.673 to 0.775), respectively), which was confirmed in the validation set. CONCLUSIONS: We propose an ICS that significantly differentiates between low-risk and high-risk patients, which might add prognostic value to age and provide clues for immunotherapy in NB. BMJ Publishing Group 2023-05-02 /pmc/articles/PMC10163522/ /pubmed/37130627 http://dx.doi.org/10.1136/jitc-2022-005980 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Immunotherapy Biomarkers Zeng, Liang Xu, Hui Li, Shu-Hua Xu, Shuo-Yu Chen, Kai Qin, Liang-Jun Miao, Lei Wang, Fang Deng, Ling Wang, Feng-Hua Li, Le Fu, Sha Liu, Na Wang, Ran Li, Ying-Qing Wang, Hai-Yun Cross-cohort analysis identified an immune checkpoint-based signature to predict the clinical outcomes of neuroblastoma |
title | Cross-cohort analysis identified an immune checkpoint-based signature to predict the clinical outcomes of neuroblastoma |
title_full | Cross-cohort analysis identified an immune checkpoint-based signature to predict the clinical outcomes of neuroblastoma |
title_fullStr | Cross-cohort analysis identified an immune checkpoint-based signature to predict the clinical outcomes of neuroblastoma |
title_full_unstemmed | Cross-cohort analysis identified an immune checkpoint-based signature to predict the clinical outcomes of neuroblastoma |
title_short | Cross-cohort analysis identified an immune checkpoint-based signature to predict the clinical outcomes of neuroblastoma |
title_sort | cross-cohort analysis identified an immune checkpoint-based signature to predict the clinical outcomes of neuroblastoma |
topic | Immunotherapy Biomarkers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10163522/ https://www.ncbi.nlm.nih.gov/pubmed/37130627 http://dx.doi.org/10.1136/jitc-2022-005980 |
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