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- Title
Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence.
- Authors
Cutrona, Giovanna; Tripodo, Claudio; Matis, Serena; Recchia, Anna Grazia; Massucco, Carlotta; Fabbi, Marina; Colombo, Monica; Emionite, Laura; Sangaletti, Sabina; Gulino, Alessandro; Reverberi, Daniele; Massara, Rosanna; Boccardo, Simona; de Totero, Daniela; Salvi, Sandra; Cilli, Michele; Pellicanò, Mariavaleria; Manzoni, Martina; Fabris, Sonia; Airoldi, Irma
- Abstract
An autocrine/paracrine loop involving IL-23 and the IL-23R complex drives CLL cell expansion and represents a potential therapeutic target. Interrupting IL-23 signaling could curb CLL: 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.
- Subjects
INTERLEUKINS; CHRONIC lymphocytic leukemia; GENE expression; LYMPHOID tissue; CELL proliferation
- Publication
Science Translational Medicine, 2018, Vol 10, Issue 428, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aal1571