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Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues

Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug’s action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironme...

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Autores principales: Fan, Teresa WM, Higashi, Richard M, Song, Huan, Daneshmandi, Saeed, Mahan, Angela L, Purdom, Matthew S, Bocklage, Therese J, Pittman, Thomas A, He, Daheng, Wang, Chi, Lane, Andrew N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476122/
https://www.ncbi.nlm.nih.gov/pubmed/34406120
http://dx.doi.org/10.7554/eLife.69578
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author Fan, Teresa WM
Higashi, Richard M
Song, Huan
Daneshmandi, Saeed
Mahan, Angela L
Purdom, Matthew S
Bocklage, Therese J
Pittman, Thomas A
He, Daheng
Wang, Chi
Lane, Andrew N
author_facet Fan, Teresa WM
Higashi, Richard M
Song, Huan
Daneshmandi, Saeed
Mahan, Angela L
Purdom, Matthew S
Bocklage, Therese J
Pittman, Thomas A
He, Daheng
Wang, Chi
Lane, Andrew N
author_sort Fan, Teresa WM
collection PubMed
description Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug’s action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients’ TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients’ native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients were treated with Pembrolizumab and/or beta-glucan (WGP, an innate immune activator). Metabolic tracing with (13)C(6)-Glc/(13)C(5),(15)N(2)-Gln, multiplex immunofluorescence, and digital spatial profiling (DSP) were employed to interrogate metabolic and functional responses to Pembrolizumab and/or WGP. Primary and BM PD-1(+) lung cancer OTC responded to Pembrolizumab and Pembrolizumab + WGP treatments, respectively. Pembrolizumab activated innate immune metabolism and functions in primary OTC, which were accompanied by tissue damage. DSP analysis indicated an overall decrease in immunosuppressive macrophages and T cells but revealed microheterogeneity in immune responses and tissue damage. Two TMEs with altered cancer cell properties showed resistance. Pembrolizumab or WGP alone had negligible effects on BM-lung cancer OTC but Pembrolizumab + WGP blocked central metabolism with increased pro-inflammatory effector release and tissue damage. In-depth metabolic analysis and multiplex TME imaging of lung cancer OTC demonstrated overall innate immune activation by Pembrolizumab but heterogeneous responses in the native TME of a patient with primary NSCLC. Metabolic and functional analysis also revealed synergistic action of Pembrolizumab and WGP in OTC of metastatic NSCLC.
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spelling pubmed-84761222021-09-29 Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues Fan, Teresa WM Higashi, Richard M Song, Huan Daneshmandi, Saeed Mahan, Angela L Purdom, Matthew S Bocklage, Therese J Pittman, Thomas A He, Daheng Wang, Chi Lane, Andrew N eLife Cancer Biology Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug’s action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients’ TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients’ native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients were treated with Pembrolizumab and/or beta-glucan (WGP, an innate immune activator). Metabolic tracing with (13)C(6)-Glc/(13)C(5),(15)N(2)-Gln, multiplex immunofluorescence, and digital spatial profiling (DSP) were employed to interrogate metabolic and functional responses to Pembrolizumab and/or WGP. Primary and BM PD-1(+) lung cancer OTC responded to Pembrolizumab and Pembrolizumab + WGP treatments, respectively. Pembrolizumab activated innate immune metabolism and functions in primary OTC, which were accompanied by tissue damage. DSP analysis indicated an overall decrease in immunosuppressive macrophages and T cells but revealed microheterogeneity in immune responses and tissue damage. Two TMEs with altered cancer cell properties showed resistance. Pembrolizumab or WGP alone had negligible effects on BM-lung cancer OTC but Pembrolizumab + WGP blocked central metabolism with increased pro-inflammatory effector release and tissue damage. In-depth metabolic analysis and multiplex TME imaging of lung cancer OTC demonstrated overall innate immune activation by Pembrolizumab but heterogeneous responses in the native TME of a patient with primary NSCLC. Metabolic and functional analysis also revealed synergistic action of Pembrolizumab and WGP in OTC of metastatic NSCLC. eLife Sciences Publications, Ltd 2021-08-18 /pmc/articles/PMC8476122/ /pubmed/34406120 http://dx.doi.org/10.7554/eLife.69578 Text en © 2021, Fan et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Fan, Teresa WM
Higashi, Richard M
Song, Huan
Daneshmandi, Saeed
Mahan, Angela L
Purdom, Matthew S
Bocklage, Therese J
Pittman, Thomas A
He, Daheng
Wang, Chi
Lane, Andrew N
Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues
title Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues
title_full Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues
title_fullStr Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues
title_full_unstemmed Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues
title_short Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues
title_sort innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476122/
https://www.ncbi.nlm.nih.gov/pubmed/34406120
http://dx.doi.org/10.7554/eLife.69578
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