Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6 blockade-refractory idiopathic multicentric Castleman disease
Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6 blockade-refractory idiopathic multicentric Castleman disease
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DOI：
10.1172/jci126091
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发表时间：
2019-10-01
影响因子：
15.9
通讯作者：
Uldrick, Thomas S.
中科院分区：
文献类型：
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作者：
Fajgenbaum, David C.;Langan, Ruth-Anne;Uldrick, Thomas S.
背景特发性多中心Castleman病（iMCD）是一种血液系统疾病，涉及尼古丁诱导的淋巴细胞增生、全身性炎症、血细胞减少和危及生命的多器官功能障碍。白细胞介素-6（IL-6）阻滞难治性患者的分子基础仍然未知;没有靶向治疗。在这项研究中，我们寻找IL-6阻断难治性iMCD患者的治疗靶点，这些患者具有血小板减少、全身水肿、发热/C反应蛋白升高、网硬蛋白骨髓纤维化、肾功能不全、器官肿大（TAFRO）临床亚型。我们分析了来自3名IL-6阻断难治性iMCD-TAFRO患者的组织和血液样品。采用细胞因子面板、定量血清蛋白质组学、PBMC的流式细胞术和途径分析来鉴定新的治疗靶点。为了确认mTOR信号传导升高（上述试验的候选治疗靶点），在3份iMCD淋巴结组织样本和对照中对磷酸化S6（mTOR活化的读数）进行免疫组织化学。进行蛋白质组学、免疫表型和临床应答评估，以量化mTOR抑制剂西罗莫司给药的影响。对3例IL-6阻断难治性iMCD病例的研究显示，CD 8（+）T细胞活化、VEGF-A和PI 3 K/Akt/mTOR通路活性增加。西罗莫司给药显著减弱了CD 8（+）T细胞活化并降低了VEGF-A水平。西罗莫司在所有3例患者中均诱导了临床获益反应，持续缓解时间分别为66、19和19个月。这种精准医学方法将PI 3 K/Akt/mTOR信号转导确定为IL-6阻断难治性iMCD中的第一个可靶向的致病过程。计划对西罗莫司治疗难治性iMCD进行前瞻性评价（NCT 03933904）。
BACKGROUND. Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6 (IL-6) blockade-refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6 blockade-refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype.METHODS. We analyzed tissues and blood samples from 3 IL-6 blockade-refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in 3 iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor sirolimus.RESULTS. Studies of 3 IL-6 blockade-refractory iMCD cases revealed increased CD8(+) T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus substantially attenuated CD8(+) T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all 3 patients with durable and ongoing remissions of 66, 19, and 19 months.CONCLUSION. This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically targetable pathogenic process in IL-6 blockade-refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904).