Acute myeloid leukemia-derived exosomes deliver miRNA to hinder the T-cell immune response

microRNAs (miRNAs) are known as potent gene expression regulators, and several studies have revealed the prognostic value of miRNAs in acute myeloid leukemia (AML) patient survival. Recently, strong evidence has indicated that miRNAs can be transported by exosomes (EXOs) from cancer cells to recipient immune microenvironment (IME) cells.

Researchers at the Université Libre de Bruxelles found that AML blast-released EXOs enhance CD3 T-cell apoptosis in both CD4 and CD8 T cells. They hypothesized that miRNAs present in EXOs are key players in mediating the changes observed in AML T-cell survival. They found that miR-24-3p, a commonly overexpressed miRNA in AML, was present in released EXOs, suggesting that EXO-miR-24-3p was linked to the increased miR-24-3p levels detected in isolated AML T cells. These results were corroborated by ex vivo-generated miR-24-3p-enriched EXOs, which showed that miR-24-3p-EXOs increased apoptosis and miR-24-3p levels in T cells. The researchers also demonstrated that overexpression of miR-24-3p increased T-cell apoptosis and affected T-cell proliferation by directly targeting DENN/MADD expression and indirectly altering the NF-κB, p-JAK/STAT, and p-ERK signaling pathways but promoting regulatory T-cell (Treg) development.

Fig. 7

Mechanistic model of the role of miR-24-3p: miR-24-3p regulates T-cell apoptosis induction. Signal I: When TNF binds to TNFR1, it leads to the activation of cell survival via the activation of the NF-κB signaling network and JAK/STAT proteins and hence apoptotic resistance. Signal II: Overexpression of miR-24-3p through derived EXOs silences DENN/MADD expression, which induces the apoptosis signaling network through the deregulation of NF-κB and JAK/STAT and ERK phosphorylation. miR-24-3p increases the expression of caspase 9 and 3, inducing apoptosis. Finally, miR-24-3p impedes T-cell function through the Jak/STAT and NF-κB signaling networks. miR-24-3p is therefore a key player in AML escape from T-cell-mediated cytotoxicity and largely contributes to blast survival

These results highlight a mechanism through which AML blasts indirectly impede T-cell function via transferred exosomal miR-24-3p. In conclusion, by characterizing the signaling network regulated by individual miRNAs in the leukemic IME, these researchers aimed to discover new nonleukemic immune targets to rescue the potent antitumor function of T cells against AML blasts.

Otmani K, Rouas R, Lagneaux L, Krayem M, Duvillier H, Berehab M, Lewalle P. (2023) Acute myeloid leukemia-derived exosomes deliver miR-24-3p to hinder the T-cell immune response through DENN/MADD targeting in the NF-κB signaling pathways. Cell Commun Signal 21(1):253. [article]

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