Lung tumours reprogram pulmonary dendritic cell immunogenicity at the microRNA level.
Lung cancer arises in a context of tumour-induced immune suppression. Dendritic cells (DCs) are central players in the induction of anti-tumoural immunity, providing critical signals that drive the induction of cytotoxic T-cell responses. Meanwhile, microRNAs are associated with tumour development as well as immune regulation. We postulated that lung tumours escape immune control by reprogramming DC immunogenicity at the microRNA level. Using an orthotopic model of lung cancer, we first identified the DC population responsible for transport and cross-presentation of lung tumour-derived antigens to naïve T cells in the draining mediastinal lymph nodes (LNs). Profiling the full microRNA repertoire of these DCs revealed a restricted set of microRNAs that was consistently dysregulated in the presence of lung tumours, with miR-301a as one of the top upregulated transcripts. Overexpression of miR-301a in DCs suppressed IL-12 secretion, decreased IFN-γ release from antigen-specific cytotoxic T cells, and shifted antigen-specific T helper cytokine profile away from IFN-γ towards IL-13 and IL-17A-secreting T cells. Strikingly, DC-selective Dicer1 gene deletion resulted in delayed lung tumour growth and a survival benefit. Taken together, our data reveal that lung tumours induce an immunosuppressive microRNA signature in pulmonary DCs. Interfering with the DC-intrinsic capacity to remodel microRNA repertoires affects lung tumour outcome.
Department of Respiratory Medicine, Tumor Immunology Laboratory, Ghent University Hospital, Ghent, Belgium; VIB Inflammation Research Center, Ghent, Belgium; Department of Respiratory Medicine, Ghent University, Ghent, Belgium.
Lotte
L
Pyfferoen
Pieter
P
Mestdagh
Karl
K
Vergote
Nancy
N
De Cabooter
Jo
J
Vandesompele
Bart N
BN
Lambrecht
Karim Y
KY
Vermaelen
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology*; D017353:Gene Deletion; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009368:Neoplasm Transplantation; D043244:Ribonuclease III / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology
D000951:Antigens, Neoplasm; D016207:Cytokines; D018793:Interleukin-13; D020381:Interleukin-17; C573832:MIRN301 microRNA, mouse; D035683:MicroRNAs; D018664:Interleukin-12; D007371:Interferon-gamma; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
Dicer; dendritic cells; lung cancer; microRNAs