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, 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.

Targeted activation of GPER enhances the efficacy of venetoclax by boosting leukemic pyroptosis and CD8+ T cell immune function in acute myeloid leukemia

“…In line with our findings, Erkes et al [ 54 ] demonstrated that mutant BRAF and MEK inhibitor-induced pyroptosis promoted T cell proliferation and contributed to the antitumor effects in melanoma. Notably, our previous study showed that tumor-derived extracellular vesicles inhibited CD8+ T cell immune function by suppressing creatine import, thereby enhancing the immune escape of NPM1mut leukemia [ 55 ]. Given the potent antileukemia capabilities of CD8+ T cells, contemporary immunotherapies aim to restore weakened T cell function in AML patients using a variety of strategies [ 56 ].…”

Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment

“…The latter targets SLC6A8-mediated creatine import and promotes immunosuppressive activities of CD8 + T cells. These observations indicate that TEV-miR-19a-3p might be a promising therapeutic target for AML carrying NPM1 mutations [ 57 ].…”

PABPC1——mRNA stability, protein translation and tumorigenesis

“…There is growing evidence that selective processing of mRNAs, including selective splicing, 3' selective polyadenylation and mRNA stability/translational regulation, is a major mechanism that promotes protein diversification (140)(141)(142)(143). Selective splicing and polyadenylation in eukaryotic cells generate multiple mRNA types with different 3'UTR lengths from the same gene (144,145).…”

“…T cells play a central role in mediating and coordinating the immune response against cancer, and many strategies aim to harness the potential of t cells to recognize and kill cancer cells in a targeted manner ( 176 , 177 ). The study found that serum from AML patients with NPM1 mutations and leukemia cells in a co-culture system impaired the immune function of CD8+ T cells ( 142 ). Mechanistically, leukemic cells secrete miR-19a-3p into the tumor microenvironment via small extracellular vesicles (sEVs), which are controlled by the NPM1 mutant protein/CTCF/PABPC1 signaling axis.…”