Leary, NoelleWalser, SarinaHe, YuliangCousin, NikolaPereira, PauloGallo, AlessandroCollado-Diaz, VictorHalin, CorneliaGarcia-Silva, SusanaPeinado Selgas, HectorDieterich, Lothar C2026-02-212026-02-212022-02J Extracell Vesicles . 2022 Feb;11(2):e12197.https://hdl.handle.net/20.500.12105/27254The authors would like to thank Jeannette Scholl, Stephan Handschin, Britta Hettich and Jean-Christoph Leroux (all ETH Zurich, Switzerland) for technical support, Steven Proulx (University of Berne, Switzerland), Kristian Ikenberg (University Hospital Zurich) and Aizea Morales (Pieris Pharmaceuticals, Munich, Germany) for helpful discussions, Tobias Bald (QIMR Berghofer, Brisbane, Australia), Sandra Ring (Cantonal Hospital St. Gallen, Switzerland), Franz Ricklefs (University Hospital Hamburg, Germany), Xandra Breakefield (Harvard Medical School, USA), Roman Sporri (ETH Zurich, Switzerland) and the NIH Tetramer Core Facility (Emory University, USA) for providing vital reagents, and Michael Detmar (ETH Zurich) for general support including research infrastructure, instruments and reagents. This work was supported by research grants from ETH Zurich, Krebsliga Zurich, and the Vontobel Foundation.Tumour-draining lymph nodes (LNs) undergo massive remodelling including expansion of the lymphatic sinuses, a process that has been linked to lymphatic metastasis by creation of a pre-metastatic niche. However, the signals leading to these changes have not been completely understood. Here, we found that extracellular vesicles (EVs) derived from melanoma cells are rapidly transported by lymphatic vessels to draining LNs, where they selectively interact with lymphatic endothelial cells (LECs) as well as medullary sinus macrophages. Interestingly, uptake of melanoma EVs by LN-resident LECs was partly dependent on lymphatic VCAM-1 expression, and induced transcriptional changes as well as proliferation of those cells. Furthermore, melanoma EVs shuttled tumour antigens to LN LECs for cross-presentation on MHC-I, resulting in apoptosis induction in antigen-specific CD8 T cells. In conclusion, our data identify EV-mediated melanoma-LN LEC communication as a new pathway involved in tumour progression and tumour immune inhibition, suggesting that EV uptake or effector mechanisms in LECs might represent a new target for melanoma therapy.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/exosomeimmunotherapylymphangiogenesispre-metastatic nichesentinel lymph nodeAttribution-NonCommercial-NoDerivatives 4.0 International35188342112e12197J Extracell Vesiclesopen access