Cargando…

The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome

Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the biology of immune cells in the lung cancer micro-environment. Dendritic cells (DCs) represent a heterogeneous and highly plastic immune cell system with a central role...

Descripción completa

Detalles Bibliográficos
Autores principales: Pyfferoen, Lotte, Brabants, Elisabeth, Everaert, Celine, De Cabooter, Nancy, Heyns, Kelly, Deswarte, Kim, Vanheerswynghels, Manon, De Prijck, Sofie, Waegemans, Glenn, Dullaers, Melissa, Hammad, Hamida, De Wever, Olivier, Mestdagh, Pieter, Vandesompele, Jo, Lambrecht, Bart N., Vermaelen, Karim Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283643/
https://www.ncbi.nlm.nih.gov/pubmed/28197369
http://dx.doi.org/10.1080/2162402X.2016.1253655
_version_ 1782503526868451328
author Pyfferoen, Lotte
Brabants, Elisabeth
Everaert, Celine
De Cabooter, Nancy
Heyns, Kelly
Deswarte, Kim
Vanheerswynghels, Manon
De Prijck, Sofie
Waegemans, Glenn
Dullaers, Melissa
Hammad, Hamida
De Wever, Olivier
Mestdagh, Pieter
Vandesompele, Jo
Lambrecht, Bart N.
Vermaelen, Karim Y.
author_facet Pyfferoen, Lotte
Brabants, Elisabeth
Everaert, Celine
De Cabooter, Nancy
Heyns, Kelly
Deswarte, Kim
Vanheerswynghels, Manon
De Prijck, Sofie
Waegemans, Glenn
Dullaers, Melissa
Hammad, Hamida
De Wever, Olivier
Mestdagh, Pieter
Vandesompele, Jo
Lambrecht, Bart N.
Vermaelen, Karim Y.
author_sort Pyfferoen, Lotte
collection PubMed
description Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the biology of immune cells in the lung cancer micro-environment. Dendritic cells (DCs) represent a heterogeneous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs are emerging as clinically relevant parameters in lung cancer. In this study, we used an orthotopic preclinical model of lung cancer to dissect how the lung tumor micro-environment affects tissue-resident DCs and extract novel biologically and clinically relevant information. Lung tumor-infiltrating leukocytes expressing generic DC markers were found to predominantly consist of CD11b(+) cells that, compare with peritumoral lung DC counterparts, strongly overexpress the T-cell inhibitory molecule PD-L1 and acquire classical surface markers of tumor-associated macrophages (TAMs). Transcriptome analysis of these CD11b(+) tumor-infiltrating DCs (TIDCs) indicates impaired antitumoral immunogenicity, confirms the skewing toward TAM-related features, and indicates exposure to a hypoxic environment. In parallel, TIDCs display a specific microRNA (miRNA) signature dominated by the prototypical lung cancer oncomir miR-31. In vitro, hypoxia drives intrinsic miR-31 expression in CD11b(+) DCs. Conditioned medium of miR-31 overexpressing CD11b(+) DCs induces pro-invasive lung cancer cell shape changes and is enriched with pro-metastatic soluble factors. Finally, analysis of TCGA datasets reveals that the TIDC-associated miRNA signature has a negative prognostic impact in non-small cell lung cancer. Together, these data suggest a novel mechanism through which the lung cancer micro-environment exploits the plasticity of the DC system to support tumoral progression.
format Online
Article
Text
id pubmed-5283643
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Taylor & Francis
record_format MEDLINE/PubMed
spelling pubmed-52836432017-02-14 The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome Pyfferoen, Lotte Brabants, Elisabeth Everaert, Celine De Cabooter, Nancy Heyns, Kelly Deswarte, Kim Vanheerswynghels, Manon De Prijck, Sofie Waegemans, Glenn Dullaers, Melissa Hammad, Hamida De Wever, Olivier Mestdagh, Pieter Vandesompele, Jo Lambrecht, Bart N. Vermaelen, Karim Y. Oncoimmunology Original Research Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the biology of immune cells in the lung cancer micro-environment. Dendritic cells (DCs) represent a heterogeneous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs are emerging as clinically relevant parameters in lung cancer. In this study, we used an orthotopic preclinical model of lung cancer to dissect how the lung tumor micro-environment affects tissue-resident DCs and extract novel biologically and clinically relevant information. Lung tumor-infiltrating leukocytes expressing generic DC markers were found to predominantly consist of CD11b(+) cells that, compare with peritumoral lung DC counterparts, strongly overexpress the T-cell inhibitory molecule PD-L1 and acquire classical surface markers of tumor-associated macrophages (TAMs). Transcriptome analysis of these CD11b(+) tumor-infiltrating DCs (TIDCs) indicates impaired antitumoral immunogenicity, confirms the skewing toward TAM-related features, and indicates exposure to a hypoxic environment. In parallel, TIDCs display a specific microRNA (miRNA) signature dominated by the prototypical lung cancer oncomir miR-31. In vitro, hypoxia drives intrinsic miR-31 expression in CD11b(+) DCs. Conditioned medium of miR-31 overexpressing CD11b(+) DCs induces pro-invasive lung cancer cell shape changes and is enriched with pro-metastatic soluble factors. Finally, analysis of TCGA datasets reveals that the TIDC-associated miRNA signature has a negative prognostic impact in non-small cell lung cancer. Together, these data suggest a novel mechanism through which the lung cancer micro-environment exploits the plasticity of the DC system to support tumoral progression. Taylor & Francis 2016-11-08 /pmc/articles/PMC5283643/ /pubmed/28197369 http://dx.doi.org/10.1080/2162402X.2016.1253655 Text en © 2017 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.
spellingShingle Original Research
Pyfferoen, Lotte
Brabants, Elisabeth
Everaert, Celine
De Cabooter, Nancy
Heyns, Kelly
Deswarte, Kim
Vanheerswynghels, Manon
De Prijck, Sofie
Waegemans, Glenn
Dullaers, Melissa
Hammad, Hamida
De Wever, Olivier
Mestdagh, Pieter
Vandesompele, Jo
Lambrecht, Bart N.
Vermaelen, Karim Y.
The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome
title The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome
title_full The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome
title_fullStr The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome
title_full_unstemmed The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome
title_short The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome
title_sort transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microrna signature with negative impact on clinical outcome
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283643/
https://www.ncbi.nlm.nih.gov/pubmed/28197369
http://dx.doi.org/10.1080/2162402X.2016.1253655
work_keys_str_mv AT pyfferoenlotte thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT brabantselisabeth thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT everaertceline thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT decabooternancy thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT heynskelly thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT deswartekim thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT vanheerswynghelsmanon thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT deprijcksofie thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT waegemansglenn thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT dullaersmelissa thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT hammadhamida thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT deweverolivier thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT mestdaghpieter thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT vandesompelejo thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT lambrechtbartn thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT vermaelenkarimy thetranscriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT pyfferoenlotte transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT brabantselisabeth transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT everaertceline transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT decabooternancy transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT heynskelly transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT deswartekim transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT vanheerswynghelsmanon transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT deprijcksofie transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT waegemansglenn transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT dullaersmelissa transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT hammadhamida transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT deweverolivier transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT mestdaghpieter transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT vandesompelejo transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT lambrechtbartn transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome
AT vermaelenkarimy transcriptomeoflungtumorinfiltratingdendriticcellsrevealsatumorsupportingphenotypeandamicrornasignaturewithnegativeimpactonclinicaloutcome