Enhanced Expression of miR-181b in B Cells of CLL Improves the Anti-Tumor Cytotoxic T Cell Response

SIMPLE SUMMARY: Low expression of miR-181b in chronic lymphocytic leukemia (CLL) is linked to progression and cell death resistance. Patients with the progression of the disease show immune dysfunction. We aim at studying whether miR-181b is also involved in this process. We demonstrate that miR-181b can be increased in CLL cells by crosstalk with CD40L(+) T cells, enhancing the maturation of CD8(+) T cells in cytotoxic T lymphocytes (CTL) and, in turn, the anti-tumor cytotoxic T cell response in in vitro and in vivo models. These results demonstrate a role of the miR-181b in the immune response against tumor and envisage a therapeutic action of miR-181b in a specific milieu surrounding CLL cells. ABSTRACT: The clinical progression of B cell chronic lymphocytic leukemia (CLL) is associated with immune cell dysfunction and a strong decrease of miR-181b-5p (miR-181b), promoting the death of CLL cells. Here we investigated whether the reduction of miR-181b impairs the immune response in CLL. We demonstrate that activated CD4+ T cells increase miR-181b expression in CLL through CD40–CD40L signaling, which enhances the maturation and activity of cytotoxic T cells and, consequently, the apoptotic response of CLL cells. The cytotoxic response is facilitated by a depletion of the anti-inflammatory cytokine interleukin 10, targeted by miR-181b. In vivo experiments in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice confirmed that miR-181b promotes the apoptotic death of CLL cells only when functional T cells are restored. Overall, our findings suggest that the reinstatement of miR-181b in CLL cells could be an exploitable adjuvant therapeutic option for the treatment of CLL.