Lung tumours reprogram pulmonary Dendritic cell immunogenicity at the microrna level
International Journal of Cancer , Volume 135 - Issue 12 p. 2868- 2877
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 antigenspecific cytotoxic T cells, and shifted antigen-specific T helper cytokine profile away from IFN-γ towards IL-13 and IL-17Asecreting 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.
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|International Journal of Cancer|
|Organisation||Department of Pulmonology|
Pyfferoen, L, Mestdagh, P, Vergote, K, De Cabooter, N, Vandesompele, J, Lambrecht, B.N.M, & Vermaelen, K.Y. (2014). Lung tumours reprogram pulmonary Dendritic cell immunogenicity at the microrna level. International Journal of Cancer, 135(12), 2868–2877. doi:10.1002/ijc.28945