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; Sebastiano 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

doi:10.3390/cancers13020257

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

Cancers (Basel). 2021 Jan 12;13(2):257. doi: 10.3390/cancers13020257.

Authors

Mirco Di Marco^{1

2}, Serena Veschi^{1

2}, Paola Lanuti^{1

3}, Alice Ramassone^{1

2}, Stefania Pacillo^{1

2}, Sara Pagotto^{1

2}, Felice Pepe^{1

2}, Jonahunnatha Nesson George-William^{1

2}, Claudia Curcio^{1

3}, Marco Marchisio^{1

3}, Sebastiano Miscia³, Idanna Innocenti⁴, Francesco Autore⁴, Barbara Vannata⁴, Patrizia Di Gregorio⁵, Mario Di Gioacchino^{1

3}, Silvia Valentinuzzi^{1

2}, Manuela Iezzi^{1

3}, Renato Mariani-Costantini^{1

2}, Luigi Maria Larocca^{4

5

6}, Luca Laurenti⁴, Angelo Veronese^{1

2}, Rosa Visone^{1

2}

Affiliations

¹ Center for Advanced Studies and Technology (CAST), G. d'Annunzio University, 66100 Chieti, Italy.
² Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, 66100 Chieti, Italy.
³ Department of Medicine and Aging Sciences, G. d'Annunzio University, 66100 Chieti, Italy.
⁴ Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.
⁵ Institute of Transfusion Medicine, "Ss. Annunziata" Hospital, 66100 Chieti, Italy.
⁶ Institute of Pathological Anatomy, Catholic University of Sacred Heart, 00168 Rome, Italy.

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.

Keywords: CD40-CD40L; CLL; cytotoxic T cells; miR-181b; microRNA.

Abstract

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