PT  - JOURNAL ARTICLE
AU  - Cutrona, Giovanna
AU  - Tripodo, Claudio
AU  - Matis, Serena
AU  - Recchia, Anna Grazia
AU  - Massucco, Carlotta
AU  - Fabbi, Marina
AU  - Colombo, Monica
AU  - Emionite, Laura
AU  - Sangaletti, Sabina
AU  - Gulino, Alessandro
AU  - Reverberi, Daniele
AU  - Massara, Rosanna
AU  - Boccardo, Simona
AU  - de Totero, Daniela
AU  - Salvi, Sandra
AU  - Cilli, Michele
AU  - Pellicanò, Mariavaleria
AU  - Manzoni, Martina
AU  - Fabris, Sonia
AU  - Airoldi, Irma
AU  - Valdora, Francesca
AU  - Ferrini, Silvano
AU  - Gentile, Massimo
AU  - Vigna, Ernesto
AU  - Bossio, Sabrina
AU  - De Stefano, Laura
AU  - Palummo, Angela
AU  - Iaquinta, Giovanni
AU  - Cardillo, Martina
AU  - Zupo, Simonetta
AU  - Cerruti, Giannamaria
AU  - Ibatici, Adalberto
AU  - Neri, Antonino
AU  - Fais, Franco
AU  - Ferrarini, Manlio
AU  - Morabito, Fortunato
TI  - Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence
AID  - 10.1126/scitranslmed.aal1571
DP  - 2018 Feb 14
TA  - Science Translational Medicine
PG  - eaal1571
VI  - 10
IP  - 428
4099  - http://stm.sciencemag.org/content/10/428/eaal1571.short
4100  - http://stm.sciencemag.org/content/10/428/eaal1571.full
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.