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A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma
Immune checkpoint blockade (ICB) expands the therapeutic options for metastatic lung cancer nowadays representing a standard frontline strategy as monotherapy or combination therapy, as well as an option in oncogene-addicted NSCLC after exhaustion of targeted therapies. Predictive markers are urgent...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808386/ https://www.ncbi.nlm.nih.gov/pubmed/33520406 http://dx.doi.org/10.1080/2162402X.2020.1860586 |
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author | Budczies, Jan Kirchner, Martina Kluck, Klaus Kazdal, Daniel Glade, Julia Allgäuer, Michael Kriegsmann, Mark Heußel, Claus-Peter Herth, Felix J. Winter, Hauke Meister, Michael Muley, Thomas Fröhling, Stefan Peters, Solange Seliger, Barbara Schirmacher, Peter Thomas, Michael Christopoulos, Petros Stenzinger, Albrecht |
author_facet | Budczies, Jan Kirchner, Martina Kluck, Klaus Kazdal, Daniel Glade, Julia Allgäuer, Michael Kriegsmann, Mark Heußel, Claus-Peter Herth, Felix J. Winter, Hauke Meister, Michael Muley, Thomas Fröhling, Stefan Peters, Solange Seliger, Barbara Schirmacher, Peter Thomas, Michael Christopoulos, Petros Stenzinger, Albrecht |
author_sort | Budczies, Jan |
collection | PubMed |
description | Immune checkpoint blockade (ICB) expands the therapeutic options for metastatic lung cancer nowadays representing a standard frontline strategy as monotherapy or combination therapy, as well as an option in oncogene-addicted NSCLC after exhaustion of targeted therapies. Predictive markers are urgently needed, since only a minority of patients benefits from ICB, while serious adverse effects of immunotoxicity may occur. The study cohort included 43 ICB-treated metastatic lung adenocarcinoma showing long-term response (n = 16), rapid progression (n = 21) or intermediate patterns of response (n = 6). Lung biopsies acquired before initiation of ICB were analyzed by targeted mRNA expression profiling of 770 genes. Level and proportions of 14 immune cell types were estimated using characteristic gene expression signatures. Abundance of B cells (HR = 0.66, p = .00074), CD45+ cells (HR = 0.61, p = .01) and total TILs (HR = 0.62, p = .025) was associated with prolonged progression-free survival after ICB treatment. In a ROC analysis, B cells (AUC = 0.77, p = .0055) and CD45+ cells (AUC = 0.73, p = .019) predicted benefit of ICB, which was not the case for PD-L1 mRNA (AUC = 0.54, p = .72) and PD-L1 protein expression (AUC = 0.68, p = .082). Clustering of 79 candidate predictive markers identified among 770 investigated genes revealed two distinct predictive clusters which included cytotoxic cell or macrophage markers, respectively. In summary, targeted gene expression profiling was feasible using routine diagnostics biopsies. This study proposes B cells and total TILs as complementary predictors of ICB benefit in NSCLC. While further preferably prospective validation is required, gene expression profiling could be integrated in the routine diagnostic work-up complementing existing NGS protocols. |
format | Online Article Text |
id | pubmed-7808386 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-78083862021-01-29 A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma Budczies, Jan Kirchner, Martina Kluck, Klaus Kazdal, Daniel Glade, Julia Allgäuer, Michael Kriegsmann, Mark Heußel, Claus-Peter Herth, Felix J. Winter, Hauke Meister, Michael Muley, Thomas Fröhling, Stefan Peters, Solange Seliger, Barbara Schirmacher, Peter Thomas, Michael Christopoulos, Petros Stenzinger, Albrecht Oncoimmunology Original Research Immune checkpoint blockade (ICB) expands the therapeutic options for metastatic lung cancer nowadays representing a standard frontline strategy as monotherapy or combination therapy, as well as an option in oncogene-addicted NSCLC after exhaustion of targeted therapies. Predictive markers are urgently needed, since only a minority of patients benefits from ICB, while serious adverse effects of immunotoxicity may occur. The study cohort included 43 ICB-treated metastatic lung adenocarcinoma showing long-term response (n = 16), rapid progression (n = 21) or intermediate patterns of response (n = 6). Lung biopsies acquired before initiation of ICB were analyzed by targeted mRNA expression profiling of 770 genes. Level and proportions of 14 immune cell types were estimated using characteristic gene expression signatures. Abundance of B cells (HR = 0.66, p = .00074), CD45+ cells (HR = 0.61, p = .01) and total TILs (HR = 0.62, p = .025) was associated with prolonged progression-free survival after ICB treatment. In a ROC analysis, B cells (AUC = 0.77, p = .0055) and CD45+ cells (AUC = 0.73, p = .019) predicted benefit of ICB, which was not the case for PD-L1 mRNA (AUC = 0.54, p = .72) and PD-L1 protein expression (AUC = 0.68, p = .082). Clustering of 79 candidate predictive markers identified among 770 investigated genes revealed two distinct predictive clusters which included cytotoxic cell or macrophage markers, respectively. In summary, targeted gene expression profiling was feasible using routine diagnostics biopsies. This study proposes B cells and total TILs as complementary predictors of ICB benefit in NSCLC. While further preferably prospective validation is required, gene expression profiling could be integrated in the routine diagnostic work-up complementing existing NGS protocols. Taylor & Francis 2021-01-11 /pmc/articles/PMC7808386/ /pubmed/33520406 http://dx.doi.org/10.1080/2162402X.2020.1860586 Text en © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Budczies, Jan Kirchner, Martina Kluck, Klaus Kazdal, Daniel Glade, Julia Allgäuer, Michael Kriegsmann, Mark Heußel, Claus-Peter Herth, Felix J. Winter, Hauke Meister, Michael Muley, Thomas Fröhling, Stefan Peters, Solange Seliger, Barbara Schirmacher, Peter Thomas, Michael Christopoulos, Petros Stenzinger, Albrecht A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma |
title | A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma |
title_full | A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma |
title_fullStr | A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma |
title_full_unstemmed | A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma |
title_short | A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma |
title_sort | gene expression signature associated with b cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808386/ https://www.ncbi.nlm.nih.gov/pubmed/33520406 http://dx.doi.org/10.1080/2162402X.2020.1860586 |
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