RT Journal Article SR Electronic T1 Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence JF Science Translational Medicine FD American Association for the Advancement of Science SP eaal1571 DO 10.1126/scitranslmed.aal1571 VO 10 IS 428 A1 Cutrona, Giovanna A1 Tripodo, Claudio A1 Matis, Serena A1 Recchia, Anna Grazia A1 Massucco, Carlotta A1 Fabbi, Marina A1 Colombo, Monica A1 Emionite, Laura A1 Sangaletti, Sabina A1 Gulino, Alessandro A1 Reverberi, Daniele A1 Massara, Rosanna A1 Boccardo, Simona A1 de Totero, Daniela A1 Salvi, Sandra A1 Cilli, Michele A1 Pellicanò, Mariavaleria A1 Manzoni, Martina A1 Fabris, Sonia A1 Airoldi, Irma A1 Valdora, Francesca A1 Ferrini, Silvano A1 Gentile, Massimo A1 Vigna, Ernesto A1 Bossio, Sabrina A1 De Stefano, Laura A1 Palummo, Angela A1 Iaquinta, Giovanni A1 Cardillo, Martina A1 Zupo, Simonetta A1 Cerruti, Giannamaria A1 Ibatici, Adalberto A1 Neri, Antonino A1 Fais, Franco A1 Ferrarini, Manlio A1 Morabito, Fortunato YR 2018 UL http://stm.sciencemag.org/content/10/428/eaal1571.abstract AB Chronic lymphocytic leukemia (CLL) cells are derived from B cells, but the exact signals that drive their expansion and survival are not completely understood. Cutrona et al. observed differential expression of the IL-23 receptor on biopsies from early-stage CLL patients, and higher expression was associated with poor prognosis. CLL cells could also produce IL-23 in vitro. The authors reasoned that the cells could produce and respond to this cytokine in a survival feedback loop and demonstrated that an anti–IL-23 antibody could slow tumor growth in a xenograft mouse model. These promising results could open up new avenues of treatment for CLL.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.