1. Tumour-derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8-mediated creatine import in NPM1-mutated acute myeloid leukaemia.
- Author
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Peng M, Ren J, Jing Y, Jiang X, Xiao Q, Huang J, Tao Y, Lei L, Wang X, Yang Z, Yang Z, Zhan Q, Lin C, Jin G, Zhang X, and Zhang L
- Subjects
- Adult, Aged, Biological Transport, Coculture Techniques methods, Female, Humans, Leukemia, Myeloid, Acute blood, Male, MicroRNAs metabolism, Middle Aged, Tumor Escape, Tumor Microenvironment immunology, CD8-Positive T-Lymphocytes immunology, Creatine metabolism, Extracellular Vesicles metabolism, Immune Tolerance, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute immunology, Mutation, Nerve Tissue Proteins metabolism, Nucleophosmin genetics, Plasma Membrane Neurotransmitter Transport Proteins metabolism, Signal Transduction immunology
- 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., (© 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)
- Published
- 2021
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