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Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer. However, their clinical benefit is limited to a minority of patients. To unravel immune-related factors that are predictive of sensitivity or resistance to immunotherapy, we performed a gene expression analysis by...

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Autores principales: Baglivo, Sara, Bianconi, Fortunato, Metro, Giulio, Gili, Alessio, Tofanetti, Francesca Romana, Bellezza, Guido, Ricciuti, Biagio, Mandarano, Martina, Teti, Valeria, Siggillino, Annamaria, Reda, Maria Sole, Chiari, Rita, Pistola, Lorenza, Sidoni, Angelo, Minotti, Vincenzo, Roila, Fausto, Ludovini, Vienna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303258/
https://www.ncbi.nlm.nih.gov/pubmed/34209514
http://dx.doi.org/10.3390/genes12070992
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author Baglivo, Sara
Bianconi, Fortunato
Metro, Giulio
Gili, Alessio
Tofanetti, Francesca Romana
Bellezza, Guido
Ricciuti, Biagio
Mandarano, Martina
Teti, Valeria
Siggillino, Annamaria
Reda, Maria Sole
Chiari, Rita
Pistola, Lorenza
Sidoni, Angelo
Minotti, Vincenzo
Roila, Fausto
Ludovini, Vienna
author_facet Baglivo, Sara
Bianconi, Fortunato
Metro, Giulio
Gili, Alessio
Tofanetti, Francesca Romana
Bellezza, Guido
Ricciuti, Biagio
Mandarano, Martina
Teti, Valeria
Siggillino, Annamaria
Reda, Maria Sole
Chiari, Rita
Pistola, Lorenza
Sidoni, Angelo
Minotti, Vincenzo
Roila, Fausto
Ludovini, Vienna
author_sort Baglivo, Sara
collection PubMed
description Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer. However, their clinical benefit is limited to a minority of patients. To unravel immune-related factors that are predictive of sensitivity or resistance to immunotherapy, we performed a gene expression analysis by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) on a total of 33 advanced NSCLC patients treated with ICI evaluating the expression levels of 365 immune-related genes. We found four genes (CD1C, HLA-DPA1, MMP2, and TLR7) downregulated (p < 0.05) and two genes (IFNB1 and MKI67) upregulated (p < 0.05) in ICI-Responders compared to ICI-Non-Responders. The Bayesian enrichment computational analysis showed a more complex interaction network that involved 10 other genes (IFNA1, TLR4, CD40, TLR2, IL12A, IL12B, TLR9, CD1E, IFNG, and HLA-DPB1) correlated with different functional groups. Five main pathways were identified (FDR < 0.0001). High TLR7 expression levels were significantly associated with a lack of response to immunotherapy (p < 0.0001) and worse outcome in terms of both PFS (p < 0.001) and OS (p = 0.03). The multivariate analysis confirmed TLR7 RNA expression as an independent predictor for both poor PFS (HR = 2.97, 95% CI, 1.16–7.6, p = 0.023) and OS (HR = 2.2, 95% CI, 1–5.08, p = 0.049). In conclusion, a high TLR7 gene expression level was identified as an independent predictor for poor clinical benefits from ICI. These data could have important implications for the development of novel single/combinatorial strategies TLR-mediated for an efficient selection of “individualized” treatments for NSCLC in the era of immunotherapy.
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spelling pubmed-83032582021-07-25 Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy Baglivo, Sara Bianconi, Fortunato Metro, Giulio Gili, Alessio Tofanetti, Francesca Romana Bellezza, Guido Ricciuti, Biagio Mandarano, Martina Teti, Valeria Siggillino, Annamaria Reda, Maria Sole Chiari, Rita Pistola, Lorenza Sidoni, Angelo Minotti, Vincenzo Roila, Fausto Ludovini, Vienna Genes (Basel) Article Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer. However, their clinical benefit is limited to a minority of patients. To unravel immune-related factors that are predictive of sensitivity or resistance to immunotherapy, we performed a gene expression analysis by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) on a total of 33 advanced NSCLC patients treated with ICI evaluating the expression levels of 365 immune-related genes. We found four genes (CD1C, HLA-DPA1, MMP2, and TLR7) downregulated (p < 0.05) and two genes (IFNB1 and MKI67) upregulated (p < 0.05) in ICI-Responders compared to ICI-Non-Responders. The Bayesian enrichment computational analysis showed a more complex interaction network that involved 10 other genes (IFNA1, TLR4, CD40, TLR2, IL12A, IL12B, TLR9, CD1E, IFNG, and HLA-DPB1) correlated with different functional groups. Five main pathways were identified (FDR < 0.0001). High TLR7 expression levels were significantly associated with a lack of response to immunotherapy (p < 0.0001) and worse outcome in terms of both PFS (p < 0.001) and OS (p = 0.03). The multivariate analysis confirmed TLR7 RNA expression as an independent predictor for both poor PFS (HR = 2.97, 95% CI, 1.16–7.6, p = 0.023) and OS (HR = 2.2, 95% CI, 1–5.08, p = 0.049). In conclusion, a high TLR7 gene expression level was identified as an independent predictor for poor clinical benefits from ICI. These data could have important implications for the development of novel single/combinatorial strategies TLR-mediated for an efficient selection of “individualized” treatments for NSCLC in the era of immunotherapy. MDPI 2021-06-29 /pmc/articles/PMC8303258/ /pubmed/34209514 http://dx.doi.org/10.3390/genes12070992 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Baglivo, Sara
Bianconi, Fortunato
Metro, Giulio
Gili, Alessio
Tofanetti, Francesca Romana
Bellezza, Guido
Ricciuti, Biagio
Mandarano, Martina
Teti, Valeria
Siggillino, Annamaria
Reda, Maria Sole
Chiari, Rita
Pistola, Lorenza
Sidoni, Angelo
Minotti, Vincenzo
Roila, Fausto
Ludovini, Vienna
Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy
title Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy
title_full Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy
title_fullStr Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy
title_full_unstemmed Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy
title_short Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy
title_sort higher tlr7 gene expression predicts poor clinical outcome in advanced nsclc patients treated with immunotherapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303258/
https://www.ncbi.nlm.nih.gov/pubmed/34209514
http://dx.doi.org/10.3390/genes12070992
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