Paediatric pre‐B acute lymphoblastic leukaemia‐derived exosomes regulate immune function in human T cells

Abstract

Exosomes derived from solid tumour cells are involved in immune suppression, angiogenesis and metastasis; however, the role of leukaemia‐derived exosomes has less been investigated. Hence, changes in immune response‐related genes and human T cells apoptosis co‐incubated with exosomes isolated from patients' pre‐B cell acute lymphoblastic leukaemia were evaluated in this in vitro study. Vein blood sample was obtained from each newly diagnosed acute lymphoblastic leukaemia (ALL) patient prior any therapy. ALL serum exosomes were isolated by ultrafiltration and characterized using Western blotting and transmission electron microscopy. Exosomes were then co‐incubated with T lymphocytes and the gene expressions, as well as functions of human T cells were quantified by qRT‐PCR. Apoptosis and caspase‐3 and caspase‐9 protein expression were also evaluated by flowcytometry and Western blotting analysis, respectively. Exosomes isolated from ALL patients affected T lymphocytes and elevated the apoptosis. Moreover, these exosomes altered the T cells profile into regulatory type by increasing the expression of FOXP3 and Tregs‐related cytokines, including TGF‐B and IL‐10. The expression level of Th17‐related transcription factors (RoRγt) and interleukins (IL‐17 and IL‐23) decreased after this treatment. According to our findings, exosomes derived from ALL patients' sera carry immunosuppressive molecules, indicating the possible effect of exosomes as liquid biomarkers for cancer staging.

Extracellular vesicles in hematological malignancies: EV-dence for reshaping the tumoral microenvironment

“…After 24h of exposure, ALL patient serum derived EVs may also induce an immunosuppressive environment by hindering T cell immunity. Upon internalization by CD8 + and CD4 + Th17 T cells, ALL EVs promote apoptosis by inducing BAX expression and decreasing Bcl2 expression ( 101 ). Likewise, a significant uptick of FoxP3 expression and immunosuppressive cytokine secretion was observed in T cells after 24h of coincubation with ALL EVs ( 101 ).…”

“…Upon internalization by CD8 + and CD4 + Th17 T cells, ALL EVs promote apoptosis by inducing BAX expression and decreasing Bcl2 expression ( 101 ). Likewise, a significant uptick of FoxP3 expression and immunosuppressive cytokine secretion was observed in T cells after 24h of coincubation with ALL EVs ( 101 ). In ALL patient samples, miR-181b-5p was significantly overexpressed in ALL blast-derived EVs compared to healthy donors and this overexpression may act in an autocrine manner to promote the proliferation and migration of other ALL cells ( 102 ).…”

Integrins and the Metastasis-like Dissemination of Acute Lymphoblastic Leukemia to the Central Nervous System

“…Numerous studies have addressed the role of exosomes in the ALL-stroma interaction [250][251][252]. Of note, adult T cell leukemia/lymphoma exosomes containing miRNAs, VEGF and the oncoprotein Tax alter the behavior of mesenchymal stem cells [252], whereas ALL exosomes containing various miRNAs play a role in the suppression of Th17 cells [253] and in the development of T-ALL cooperating with NOTCH1-signaling [254][255][256]. However, only a few studies have addressed the role of exosomes in leukemic dissemination to CNS.…”