Molecular Pathology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera Universitaria (AOU) San Martino-Istituto Nazionale per la Ricerca sul Cancro (IST), 16132 Genoa, Italy.
Tumor Immunology Unit, Department of Health Science, Human Pathology Section, University of Palermo School of Medicine, 90127 Palermo, Italy.
Sci Transl Med. 2018 Feb 14;10(428). doi: 10.1126/scitranslmed.aal1571.
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.
尽管慢性淋巴细胞白血病 (CLL) 的进展需要微环境的合作，但涉及的确切细胞和分子机制仍不清楚。我们研究了白细胞介素 (IL)-23 受体 (IL-23R)/IL-23 轴，发现早期 CLL 患者的循环细胞（这些患者的治疗时间较短，但疾病过程并非良性）表达一种缺乏 IL-12Rβ1 链的 IL-23R 复合物的缺陷形式。然而，两组患者的细胞在组织浸润中均表达完整的 IL-23R 复合物，并且当与激活的 T 细胞或 CD40L 细胞共培养时，可以诱导表达 IL-12Rβ1 链。在此背景下体外激活的 CLL 细胞产生 IL-23，这一发现以及 CLL 淋巴组织中存在 IL-23，表明存在诱导 CLL 细胞增殖的自分泌/旁分泌环。使用抗 IL-23p19 抗体干扰 IL-23R/IL-23 轴在异种移植小鼠中有效控制疾病的发生和扩展，提示存在潜在的治疗策略。
