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Abstract
Metastatic cancers produce exosomes that condition pre-metastatic niches in remote microenvironments to favor metastasis. In contrast, here we show that exosomes from poorly metastatic melanoma cells can potently inhibit metastasis to the lung. These “non-metastatic” exosomes stimulate an innate immune response through the expansion of Ly6Clow patrolling monocytes (PMo) in the bone marrow, which then cause cancer cell clearance at the pre-metastatic niche, via the recruitment of NK cells and TRAIL-dependent killing of melanoma cells by macrophages. These events require the induction of the Nr4a1 transcription factor and are dependent on pigment epithelium-derived factor (PEDF) on the outer surface of exosomes. Importantly, exosomes isolated from patients with non-metastatic primary melanomas have a similar ability to suppress lung metastasis. This study thus demonstrates that pre-metastatic tumors produce exosomes, which elicit a broad range of PMo-reliant innate immune responses via trigger(s) of immune surveillance, causing cancer cell clearance at the pre-metastatic niche.
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1 Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Simpson-Querrey Institute for Bionantechnology in Medicine, Chicago, IL, USA
2 Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
3 The Department for Health and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA
4 Department of Urology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
5 Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
6 Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA
7 Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
8 The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA; Laura and Isaac Perlmutter Cancer Center, New York University, Langone Medical Center, New York, NY, USA
9 Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Simpson-Querrey Institute for Bionantechnology in Medicine, Chicago, IL, USA; Northwestern University International Institute for Nanotechnology, Evanston, IL, USA