Abstract :
[en] Small extracellular vesicle (sEV, or exosome) communication among cells in the tumor microenvironment has been modeled mainly in cell culture, whereas their relevance in cancer pathogenesis and progression in vivo is less characterized. Here we investigated cancer-microenvironment interactions in vivo using mouse models of chronic lymphocytic leukemia (CLL). sEVs isolated directly from CLL tissue were enriched in specific miRNA and immune-checkpoint ligands. Distinct molecular components of tumor-derived sEVs altered CD8+ T-cell transcriptome, proteome, and metabolome, leading to decreased functions and cell exhaustion ex vivo and in vivo. Using antagomiRs and blocking antibodies, we defined specific cargo-mediated alterations on CD8+ T cells. Abrogating sEV biogenesis by Rab27a/b knockout dramatically delayed CLL pathogenesis. This phenotype was rescued by exogenous leukemic sEV or CD8+ T-cell depletion. Finally, high expression of sEV-related genes correlated with poor outcomes in CLL patients, suggesting sEV profiling as a prognostic tool. In conclusion, sEVs shape the immune microenvironment during CLL progression.
Funding text :
G. Dittmar reports grants from Luxembourg National Research Fund (FNR) during the conduct of the study. J. Meiser reports grants from Luxembourg Research Foundation during the conduct of the study; grants from FNR-ATTRACT outside the submitted work. No disclosures were reported by the other authors.We thank Pr. Carlo Croce and Pr. John Byrd (Ohio State University) for the kind gift of Eμ-TCL1 mouse, and Pr. Miguel Seabra and Dr Tanya Tolmachova (Imperial College London, UK) for the RAB27DKO mouse. We thank Dr Javier Alves Ferreira (JAF, Laboratoire National de Santé, Luxembourg) for the histopathology expertise. We thank the National Cytometry Platform (LIH; Dr Antonio Cosma, Dr Céline Hoffmann, Thomas Cerutti, Fanny Hedin, and Maria Konstantinou) for assistance in flow cytometry, imaging flow cytometry, confocal microscopy and FACS experiments, the LUXGEN platform (LIH/LNS; Nathalie Nicot, Elise Mommaerts, Arnaud Muller and Dr Daniel Stieber) for RNA sequencing, the bioinformatics platform (LIH; Tony Kaoma and Kim Sang Yoon) for assistance, and the Animal Facility (LIH) staff. We thank the Metabolomics Platform (University of Luxembourg, Christian Jäger) for GC-MS measurements and Xiangyi Dong and Floriane Vanhalle for providing technical and analytical support. Furthermore, we thank the Metabolomics core facility (LIH, Antoine Lesur and François Bernardin) for technical and analytical support. Special thanks to Dr Martina Seiffert (DKFZ, Germany) for the useful scientific discussions and for providing the Eμ-TCL1 animals. Finally, we thank Dr Marina Wierz, Bil-gee Bayanaa, and Sandrine Pierson (LIH) for technical support. This work was supported by grants from the Luxembourg National Research Fund (FNR) to E. Gargiulo, E. Moussay, and J. Paggetti (PRIDE15/10675146/ CANBIO, INTER/DFG/16/11509946, C20/BM/14582635, and C20/ BM/14592342), to J. Meiser (ATTRACT grant A18/BM/11809970), and to M. Mittelbronn (PEARL grant P16/BM/11192868), from FNRS-Télévie to E. Viry, P.E. Morande, A. Largeot, and S. Gonder (7.4509.20, 7.8506.19, 7.4503.19, and 7.6604.21), from the European Commission to P.E. Morande (H2020-MSCA-IF-2020: 101029602).We thank Pr. Carlo Croce and Pr. John Byrd (Ohio State University) for the kind gift of Eμ-TCL1 mouse, and Pr. Miguel Seabra and Dr Tanya Tolmachova (Imperial College London, UK) for the RAB27DKO mouse. We thank Dr Javier Alves Ferreira (JAF, Laboratoire National de Santé, Luxembourg) for the histopathology expertise. We thank the National Cytometry Platform (LIH; Dr Antonio Cosma, Dr Céline Hoffmann, Thomas Cerutti, Fanny Hedin, and Maria Konstantinou) for assistance in flow cytometry, imaging flow cytometry, confocal microscopy and FACS experiments, the LUXGEN platform (LIH/LNS; Nathalie Nicot, Elise Mommaerts, Arnaud Muller and Dr Daniel Stieber) for RNA sequencing, the bioinformatics platform (LIH; Tony Kaoma and Kim Sang Yoon) for assistance, and the Animal Facility (LIH) staff. We thank the Metabolomics Platform (University of Luxembourg, Christian Jäger) for GC-MS measurements and Xiangyi Dong and Floriane Vanhalle for providing technical and analytical support. Furthermore, we thank the Metabolomics core facility (LIH, Antoine Lesur and François Bernardin) for technical and analytical support. Special thanks to Dr Martina Seiffert (DKFZ, Germany) for the useful scientific discussions and for providing the Eμ-TCL1 animals. Finally, we thank Dr Marina Wierz, Bilgee Bayanaa, and Sandrine Pierson (LIH) for technical support. This work was supported by grants from the Luxembourg National Research Fund (FNR) to E. Gargiulo, E. Moussay, and J. Paggetti (PRIDE15/10675146/CANBIO, INTER/DFG/16/11509946, C20/BM/14582635, and C20/BM/14592342), to J. Meiser (ATTRACT grant A18/BM/11809970), and to M. Mittelbronn (PEARL grant P16/BM/11192868), from FNRSTélévie to E. Viry, P.E. Morande, A. Largeot, and S. Gonder (7.4509.20, 7.8506.19, 7.4503.19, and 7.6604.21), from the European Commission to P.E. Morande (H2020-MSCA-IF-2020: 101029602).
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