Tumour-derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8-mediated creatine import in NPM1-mutated acute myeloid leukaemia


Posted: 2021-11-22 20:00:00
J Extracell Vesicles . 2021 Nov;10(13):e12168. doi: 10.1002/jev2.12168. Meixi Peng 1 , Jun Ren 1 , Yipei Jing 1 , Xueke Jiang 1 , Qiaoling Xiao 1 , Junpeng Huang 1 , Yonghong Tao 1 , Li Lei 1 , Xin Wang 2 , Zailin Yang 3 4 , Zesong Yang 2 , Qian Zhan 5 , Can Lin 1 , Guoxiang Jin 6 , Xian Zhang 7 , Ling Zhang 1 Affiliations Expand Affiliations 1 Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China. 2 Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 3 Department of Clinical Laboratory, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China. 4 Chongqing University Cancer Hospital, Chongqing, China. 5 The Center for Clinical Molecular Medical detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 6 Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. 7 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. Item in Clipboard Meixi Peng et al. J Extracell Vesicles. 2021 Nov. Show details Display options Display options Format J Extracell Vesicles . 2021 Nov;10(13):e12168. doi: 10.1002/jev2.12168. Authors Meixi Peng 1 , Jun Ren 1 , Yipei Jing 1 , Xueke Jiang 1 , Qiaoling Xiao 1 , Junpeng Huang 1 , Yonghong Tao 1 , Li Lei 1 , Xin Wang 2 , Zailin Yang 3 4 , Zesong Yang 2 , Qian Zhan 5 , Can Lin 1 , Guoxiang Jin 6 , Xian Zhang 7 , Ling Zhang 1 Affiliations 1 Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China. 2 Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 3 Department of Clinical Laboratory, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China. 4 Chongqing University Cancer Hospital, Chongqing, China. 5 The Center for Clinical Molecular Medical detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 6 Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. 7 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. Item in Clipboard CiteDisplay options Display options Format Abstract Acute myeloid leukaemia (AML) carrying nucleophosmin (NPM1) mutations has been defined as a distinct entity of acute leukaemia. Despite remarkable improvements in diagnosis and treatment, the long-term outcomes for this entity remain unsatisfactory. Emerging evidence suggests that leukaemia, similar to other malignant diseases, employs various mechanisms to evade killing by immune cells. However, the mechanism of immune escape in NPM1-mutated AML remains unknown. In this study, both serum and leukemic cells from patients with NPM1-mutated AML impaired the immune function of CD8+ T cells in a co-culture system. Mechanistically, leukemic cells secreted miR-19a-3p into the tumour microenvironment (TME) via small extracellular vesicles (sEVs), which was controlled by the NPM1-mutated protein/CCCTC-binding factor (CTCF)/poly (A)-binding protein cytoplasmic 1 (PABPC1) signalling axis. sEV-related miR-19a-3p was internalized by CD8+ T cells and directly repressed the expression of solute-carrier family 6 member 8 (SLC6A8; a creatine-specific transporter) to inhibit creatine import. Decreased creatine levels can reduce ATP production and impair CD8+ T cell immune function, leading to immune escape by leukemic cells. In summary, leukemic cell-derived sEV-related miR-19a-3p confers immunosuppression to CD8+ T cells by targeting SLC6A8-mediated creatine import, indicating that sEV-related miR-19a-3p might be a promising therapeutic target for NPM1-mutated AML. Keywords: AML; CD8+ T cells; creatine; extracellular vesicles; nucleophosmin. © 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles. References REFERENCES Abreu, R. C., Ramos, C. V., Becher, C., Lino, M., Jesus, C., Costa Martins, P. A., Martins, P. A. T., Moreno, M. J., Fernandes, H., & Ferreira, L. (2021).Exogenous loading of miRNAs into small extracellular vesicles. Journal of Extracellular Vesicles, 10(10), e12111. Alfieri, R. R., Bonelli, M. A., Cavazzoni, A., Brigotti, M., Fumarola, C., Sestili, P., Mozzoni, P., De Palma, G., Mutti, A., Carnicelli, D., Vacondio, F., Silva, C., Borghetti, A. F., Wheeler, K. P., & Petronini, P. G. (2006).Creatine as a compatible osmolyte in muscle cells exposed to hypertonic stress. The Journal of Physiology, 576(Pt 2), 391-401. Berraondo, P., Sanmamed, M. F., Ochoa, M. C., Etxeberria, I., Aznar, M. A., Pérez-Gracia, J. L., Rodríguez-Ruiz, M. E., Ponz-Sarvise, M., Castañón, E., & Melero, I. (2019).Cytokines in clinical cancer immunotherapy. 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