Microenvironmental regulation of the IL-23R/IL-23 axis overrides chronic lymphocytic leukemia indolence

Abstract

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.

Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role

“…IL-21 Antitumoral Increased apoptosis [55][56][57][58][59][60] Increased proliferation of cytotoxic T cells [61,62] IL-22 Protumoral Stimulation of STAT3 [63][64][65][66] Reduced apoptosis [63][64][65][66] IL-23 Protumoral Unclear [67] TNF-alpha Protumoral Increased proliferation [68,69] STAT: Signal Transducer and Activator of Transcription; INKT: invariant Natural Killer; VEGF: Vascular Endothelial Cell Growth Factor; BCL-2: B-cell lymphoma 2; NK: Natura Killer; IL: Interleukin; TNF: Tumour Necrosis Factor.…”

“…This result indicates the presence of an autocrine/paracrine loop stimulating B-CLL cell growth. Interfering with the IL-23R/IL-23 pathway using an anti-IL-23p19 antibody was efficient in avoiding the start of the disease, suggesting possible therapeutic approaches [67].…”

TP53 dysfunction in chronic lymphocytic leukemia: clinical relevance in the era of B-cell receptors and BCL-2 inhibitors

“…It remains to be clarified whether such selection also occurs with the new biological therapies and what are the mechanisms involved. As already mentioned, a dysfunction of the p53 pathway causes a diminished response of the BCR to stimulation [77], although clonal expansion could still be facilitated by signals delivered through the JAK/STAT pathway, as it occurs for IL23 stimulation of CLL cells, which is BCR-independent [86]. BCR inhibitors can be less effective in these conditions and the expansion of subclones with TP53 dysfunction could be favoured.…”

Human pluripotent stem cells identify molecular targets of trisomy 12 in chronic lymphocytic leukemia patients

“…tri12 CLL has previously been shown to possess unique properties (Abruzzo et al, 2018;Autore et al, 2019;Beekman et al, 2018;Bulian et al, 2017;Decker et al, 2012;Fiorcari et al, 2019;Vendramini et al, 2019;Zucchetto et al, 2013), but targeted therapies have not arisen. Tumor microenvironment (Cutrona et al, 2018), B cell receptor (BCR) signaling (Smith et al, 2020), and epigenetic regulation (Gaiti et al, 2019) are important considerations that affect CLL disease pathogenesis. These factors, in addition to treatment history and patient background, may contribute to the difficulty in target identification using CLL patient-derived cells.…”