Enhanced Expression of miR-181b in B Cells of CLL Improves the Anti-Tumor Cytotoxic T Cell Response
Mirco Di Marco, Serena Veschi, Paola Lanuti, Alice Ramassone, Stefania Pacillo, Sara Pagotto, Felice Pepe, Jonahunnatha Nesson George-William, Claudia Curcio, Marco Marchisio, Sebastianó Miscia, Idanna Innocenti, Francesco Autore, Barbara Vannata, Patrizia Di Gregorio, Mario Di Gioacchino, Silvia Valentinuzzi, Manuela Iezzi, Renato Mariani‐Costantini, Luigi Maria Larocca, Luca Laurenti, Angelo Veronese, Rosa Visone
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.