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.