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- Title
Enhanced Expression of miR-181b in B Cells of CLL Improves the Anti-Tumor Cytotoxic T Cell Response.
- Authors
Di Marco, Mirco; Veschi, Serena; Lanuti, Paola; Ramassone, Alice; Pacillo, Stefania; Pagotto, Sara; Pepe, Felice; George-William, Jonahunnatha Nesson; Curcio, Claudia; Marchisio, Marco; Miscia, Sebastiano; Innocenti, Idanna; Autore, Francesco; Vannata, Barbara; Di Gregorio, Patrizia; Di Gioacchino, Mario; Valentinuzzi, Silvia; Iezzi, Manuela; Mariani-Costantini, Renato; Larocca, Luigi Maria
- Abstract
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. 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.
- Subjects
CHRONIC lymphocytic leukemia treatment; APOPTOSIS; B cells; CELLULAR signal transduction; CHRONIC lymphocytic leukemia; INTERLEUKINS; MICE; T cells; CYTOTOXINS; MICRORNA; IN vivo studies
- Publication
Cancers, 2021, Vol 13, Issue 2, p257
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers13020257