Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence

Giovanna Cutrona, Claudio Tripodo, Serena Matis, Anna Grazia Recchia, Carlotta Massucco, Marina Fabbi, Monica Colombo, Laura Emionite, Sabina Sangaletti, Alessandro Gulino, Daniele Reverberi, Rosanna Massara, Simona Boccardo, Daniela de Totero, Sandra Salvi, Michele Cilli, Mariavaleria Pellicanò, Martina Manzoni, Sonia Fabris, Irma AiroldiFrancesca Valdora, Silvano Ferrini, Massimo Gentile, Ernesto Vigna, Sabrina Bossio, Laura De Stefano, Angela Palummo, Giovanni Iaquinta, Martina Cardillo, Simonetta Zupo, Giannamaria Cerruti, Adalberto Ibatici, Antonino Neri, Franco Fais, Manlio Ferrarini, Fortunato Morabito

Research output: Contribution to journalArticle

Abstract

Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rβ1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rβ1 chain when cocultured with activated T cells or CD40L+ cells. CLL cells activated in vitro in this context produced IL-23, a finding that, together with the presence of IL-23 in CLL lymphoid tissues, suggests the existence of an autocrine/paracrine loop inducing CLL cell proliferation. Interference with the IL-23R/IL-23 axis using an anti-IL-23p19 antibody proved effective in controlling disease onset and expansion in xenografted mice, suggesting potential therapeutic strategies.

Original languageEnglish
JournalScience Translational Medicine
Volume10
Issue number428
DOIs
Publication statusPublished - Feb 14 2018

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    Cutrona, G., Tripodo, C., Matis, S., Recchia, A. G., Massucco, C., Fabbi, M., Colombo, M., Emionite, L., Sangaletti, S., Gulino, A., Reverberi, D., Massara, R., Boccardo, S., de Totero, D., Salvi, S., Cilli, M., Pellicanò, M., Manzoni, M., Fabris, S., ... Morabito, F. (2018). Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence. Science Translational Medicine, 10(428). https://doi.org/10.1126/scitranslmed.aal1571