6533b874fe1ef96bd12d6247
RESEARCH PRODUCT
Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence
Rosanna MassaraErnesto VignaAlessandro GulinoAdalberto IbaticiMartina CardilloFortunato MorabitoCarlotta MassuccoMarina FabbiAnna Grazia RecchiaFranco FaisDaniele ReverberiMariavaleria PellicanòSabrina BossioSimona BoccardoSilvano FerriniMonica ColomboSandra SalviSerena MatisGiannamaria CerrutiMartina ManzoniMartina ManzoniMassimo GentileAntonino NeriAntonino NeriLaura EmioniteSabina SangalettiClaudio TripodoSimonetta ZupoGiovanna CutronaDaniela De ToteroLaura De StefanoSonia FabrisAngela PalummoFrancesca ValdoraMichele CilliIrma AiroldiGiovanni IaquintaManlio Ferrarinisubject
0301 basic medicineStromal cellChronic lymphocytic leukemiaBiologyInterleukin-2303 medical and health sciencesParacrine signallingMice0302 clinical medicineRisk Factorshemic and lymphatic diseasesCell Line TumormedicineTumor MicroenvironmentAnimalsHumansAutocrine signallingCell ProliferationNeoplasm StagingTumor microenvironmentCD40Medicine (all)InterleukinGeneral MedicineReceptors Interleukinmedicine.diseaseAntibodies NeutralizingLeukemia Lymphocytic Chronic B-CellUp-RegulationLeukemia030104 developmental biology030220 oncology & carcinogenesisCancer researchbiology.proteinLymph NodesStromal CellsSignal Transductiondescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-01-01 |