Title : Restoring miR-181b enhances antitumor immunity in CLL: Implications for vaccine-based therapeutic strategies

Chronic lymphocytic leukemia (CLL) progression is associated with profound immune dysfunction and a marked reduction of miR-181b-5p (miR-181b), a microRNA involved in leukemic cell apoptosis and immune regulation. Here, we investigated whether restoration of miR-181b may improve the ability of CLL cells to support an effective antitumor T-cell response, providing a rationale for its exploitation in immunotherapeutic and vaccine-based strategies.

We demonstrated that activated CD4+ T cells induce miR-181b expression in CLL cells through CD40CD40L signaling. In turn, increased miR-181b promotes cytotoxic T-cell maturation and activity, enhancing CLL-cell apoptosis. This immune response is further supported by miR-181b-mediated downregulation of the immunosuppressive cytokine IL-10. Consistently, in vivo experiments demonstrated that miR-181b promotes CLL-cell apoptosis only when functional T cells are present, highlighting the immune-dependent nature of its antileukemic activity.

We further found that therapeutic modulation can restore this pathway. In patients receiving the BTK inhibitor ibrutinib, miR-181a/b expression increased during treatment and was associated with decreased leukemic burden and clinical response. Moreover, ibrutinib directly induced miR-181a/b expression and reduced CLLcell viability in vitro.

Together, these findings identify miR-181b as a potential molecular bridge between leukemic cells and antitumor T-cell immunity. Pharmacological or therapeutic restoration of miR-181b could therefore help counteract CLL-associated immunosuppression and potentially enhance the efficacy of vaccine-based approaches, including strategies aimed at generating durable tumor-specific T-cell responses.

Prof. Rosa Visone is Associate Professor at the “G. d’Annunzio” University of Chieti, Italy, with a PhD in Molecular Oncology and Endocrinology. Her research focuses on the molecular pathogenesis and immune regulation of chronic lymphocytic leukemia (CLL), with particular emphasis on microRNAs. Her studies identified miR-181b as a biomarker of CLL progression and demonstrated its role in enhancing antitumor T-cell responses. She has extensive international research experience, including at The Ohio State University, and recently completed advanced training in GMP-compliant cell and advanced therapies at the Clínica Universidad de Navarra.