Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia
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...
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Taylor & Francis Group
2021
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oai:doaj.org-article:cb84c96563384f6794e5ae30574aab8d2021-11-24T14:04:30ZTumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia2001-307810.1002/jev2.12168https://doaj.org/article/cb84c96563384f6794e5ae30574aab8d2021-11-01T00:00:00Zhttps://doi.org/10.1002/jev2.12168https://doaj.org/toc/2001-3078Abstract 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.Meixi PengJun RenYipei JingXueke JiangQiaoling XiaoJunpeng HuangYonghong TaoLi LeiXin WangZailin YangZesong YangQian ZhanCan LinGuoxiang JinXian ZhangLing ZhangTaylor & Francis GrouparticleAMLCD8+ T cellscreatineextracellular vesiclesnucleophosminCytologyQH573-671ENJournal of Extracellular Vesicles, Vol 10, Iss 13, Pp n/a-n/a (2021) |
| institution |
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DOAJ |
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EN |
| topic |
AML CD8+ T cells creatine extracellular vesicles nucleophosmin Cytology QH573-671 |
| spellingShingle |
AML CD8+ T cells creatine extracellular vesicles nucleophosmin Cytology QH573-671 Meixi Peng Jun Ren Yipei Jing Xueke Jiang Qiaoling Xiao Junpeng Huang Yonghong Tao Li Lei Xin Wang Zailin Yang Zesong Yang Qian Zhan Can Lin Guoxiang Jin Xian Zhang Ling Zhang Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia |
| description |
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. |
| format |
article |
| author |
Meixi Peng Jun Ren Yipei Jing Xueke Jiang Qiaoling Xiao Junpeng Huang Yonghong Tao Li Lei Xin Wang Zailin Yang Zesong Yang Qian Zhan Can Lin Guoxiang Jin Xian Zhang Ling Zhang |
| author_facet |
Meixi Peng Jun Ren Yipei Jing Xueke Jiang Qiaoling Xiao Junpeng Huang Yonghong Tao Li Lei Xin Wang Zailin Yang Zesong Yang Qian Zhan Can Lin Guoxiang Jin Xian Zhang Ling Zhang |
| author_sort |
Meixi Peng |
| title |
Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia |
| title_short |
Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia |
| title_full |
Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia |
| title_fullStr |
Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia |
| title_full_unstemmed |
Tumour‐derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8‐mediated creatine import in NPM1‐mutated acute myeloid leukaemia |
| title_sort |
tumour‐derived small extracellular vesicles suppress cd8+ t cell immune function by inhibiting slc6a8‐mediated creatine import in npm1‐mutated acute myeloid leukaemia |
| publisher |
Taylor & Francis Group |
| publishDate |
2021 |
| url |
https://doaj.org/article/cb84c96563384f6794e5ae30574aab8d |
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