title: The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome.
abstract: 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.
authors.affiliation: Tumor Immunology Laboratory, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: Lotte
authors.initials: L
authors.lastname: Pyfferoen
authors.affiliation: Tumor Immunology Laboratory, Department of Respiratory Medicine, Ghent University Hospital , Ghent, Belgium.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brabants
authors.affiliation: Center for Medical Genetics, Ghent University , Ghent, Belgium.
authors.forename: Celine
authors.initials: C
authors.lastname: Everaert
authors.affiliation: Tumor Immunology Laboratory, Department of Respiratory Medicine, Ghent University Hospital , Ghent, Belgium.
authors.forename: Nancy
authors.initials: N
authors.lastname: De Cabooter
authors.affiliation: Tumor Immunology Laboratory, Department of Respiratory Medicine, Ghent University Hospital , Ghent, Belgium.
authors.forename: Kelly
authors.initials: K
authors.lastname: Heyns
authors.affiliation: VIB Inflammation Research Center , Ghent, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: Deswarte
authors.affiliation: VIB Inflammation Research Center , Ghent, Belgium.
authors.forename: Manon
authors.initials: M
authors.lastname: Vanheerswynghels
authors.affiliation: VIB Inflammation Research Center , Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: De Prijck
authors.affiliation: Laboratory of Experimental Cancer Research, Ghent University , Ghent, Belgium.
authors.forename: Glenn
authors.initials: G
authors.lastname: Waegemans
authors.affiliation: Tumor Immunology Laboratory, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium; VIB Inflammation Research Center, Ghent, Belgium.
authors.forename: Melissa
authors.initials: M
authors.lastname: Dullaers
authors.affiliation: VIB Inflammation Research Center , Ghent, Belgium.
authors.forename: Hamida
authors.initials: H
authors.lastname: Hammad
authors.affiliation: Laboratory of Experimental Cancer Research, Ghent University , Ghent, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
authors.affiliation: Center for Medical Genetics, Ghent University , Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.affiliation: Center for Medical Genetics, Ghent University , Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.affiliation: VIB Inflammation Research Center, Ghent, Belgium; Department of Pulmonary Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.affiliation: Tumor Immunology Laboratory, Department of Respiratory Medicine, Ghent University Hospital , Ghent, Belgium.
authors.forename: Karim Y
authors.initials: KY
authors.lastname: Vermaelen
keywords: Dendritic cell; PD-L1; hypoxia; lung cancer; miR-31