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:	Teresa WM Fan, Richard M Higashi, Huan Song, Saeed Daneshmandi, Angela L Mahan, Matthew S Purdom, Therese J Bocklage, Thomas A Pittman, Daheng He, Chi Wang, Andrew N Lane
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	non small cell lung cancer tumor microenvironment human macrophage metabolism stable isotope resolved metabolomics pembrolizumab Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/6541a0fc470f4f33989f246beecdeb72
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spelling	oai:doaj.org-article:6541a0fc470f4f33989f246beecdeb722021-11-29T12:13:36ZInnate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues10.7554/eLife.695782050-084Xe69578https://doaj.org/article/6541a0fc470f4f33989f246beecdeb722021-08-01T00:00:00Zhttps://elifesciences.org/articles/69578https://doaj.org/toc/2050-084XAlthough 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 13C6-Glc/13C5,15N2-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.Teresa WM FanRichard M HigashiHuan SongSaeed DaneshmandiAngela L MahanMatthew S PurdomTherese J BocklageThomas A PittmanDaheng HeChi WangAndrew N LaneeLife Sciences Publications Ltdarticlenon small cell lung cancertumor microenvironmenthuman macrophage metabolismstable isotope resolved metabolomicspembrolizumabMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	non small cell lung cancer tumor microenvironment human macrophage metabolism stable isotope resolved metabolomics pembrolizumab Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	non small cell lung cancer tumor microenvironment human macrophage metabolism stable isotope resolved metabolomics pembrolizumab Medicine R Science Q Biology (General) QH301-705.5 Teresa WM Fan Richard M Higashi Huan Song Saeed Daneshmandi Angela L Mahan Matthew S Purdom Therese J Bocklage Thomas A Pittman Daheng He Chi Wang Andrew N Lane Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues
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 13C6-Glc/13C5,15N2-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.
format	article
author	Teresa WM Fan Richard M Higashi Huan Song Saeed Daneshmandi Angela L Mahan Matthew S Purdom Therese J Bocklage Thomas A Pittman Daheng He Chi Wang Andrew N Lane
author_facet	Teresa WM Fan Richard M Higashi Huan Song Saeed Daneshmandi Angela L Mahan Matthew S Purdom Therese J Bocklage Thomas A Pittman Daheng He Chi Wang Andrew N Lane
author_sort	Teresa WM Fan
title	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_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_sort	innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/6541a0fc470f4f33989f246beecdeb72
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_version_	1718407403658018816

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

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