JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation
JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation
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DOI：
10.1182/blood.2020006075
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发表时间：
2020-08-06
期刊：
影响因子：
20.3
通讯作者：
Nichols, Kim E.
中科院分区：
文献类型：
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作者：
Meyer, Lauren K.;Verbist, Katherine C.;Nichols, Kim E.
细胞因子风暴综合征 (CSS) 是一种严重的炎症性疾病，其特征是免疫系统过度激活，导致器官损伤和死亡。噬血细胞性淋巴组织细胞增多症 (HLH) 是一种通常与细胞介导的细胞毒性遗传缺陷相关的疾病，是一种典型的 CSS，其 5 年生存率仅为 60%。 HLH 的一线治疗包括糖皮质激素地塞米松 (DEX) 和化疗药物依托泊苷。然而，许多患者对这种治疗耐药，或者在初次缓解后复发。值得注意的是，HLH 中升高的许多细胞因子会激活 JAK/STAT 通路，而 JAK1/2 抑制剂鲁索替尼 (RUX) 已在小鼠 HLH 模型和患有难治性疾病的人类中显示出疗效。我们最近报道，细胞因子诱导的 JAK/STAT 信号传导介导 T 细胞急性淋巴细胞白血病 (T-ALL) 细胞对 DEX 耐药，并且 RUX 可以有效逆转这一现象。基于这些发现，我们假设细胞因子介导的 JAK/STAT 信号传导可能类似地导致 HLH 中的 DEX 耐药，而 RUX 治疗将克服这种现象。使用离体测定、HLH 小鼠模型和原发患者样本，我们证明 HLH 的高细胞因子血症降低了 CD8 T 细胞的凋亡潜力，导致相对的 DEX 耐药。暴露于 RUX 后，这种凋亡潜力得以恢复，从而使 CD8 T 细胞在体外对 DEX 诱导的细胞凋亡敏感，并在体内显着减少组织免疫病理学和 HLH 疾病表现。我们的研究结果为结合 DEX 和 RUX 以增强 DEX 的淋巴毒性作用，从而改善 HLH 和相关 CSS 患者的预后提供了理论基础。
Cytokine storm syndromes (CSS) are severe hyperinflammatory conditions characterized by excessive immune system activation leading to organ damage and death. Hemopha-gocytic lymphohistiocytosis (HLH), a disease often associated with inherited defects in cell -mediated cytotoxicity, serves as a prototypical CSS for which the 5-year survival is only 60%. Frontline therapy for HLH consists of the glucocorticoid dexamethasone (DEX) and the chemotherapeutic agent etoposide. Many patients, however, are refractory to this treatment or relapse after an initial response. Notably, many cytokines that are elevated in HLH activate the JAK/STAT pathway, and the JAK1/2 inhibitor ruxolitinib (RUX) has shown efficacy in murine HLH models and humans with refractory disease. We recently reported that cytokine-induced JAK/STAT signaling mediates DEX resistance in T cell acute lym-phoblastic leukemia (T-ALL) cells, and that this could be effectively reversed by RUX. On the basis of these findings, we hypothesized that cytokine-mediated JAK/STAT signaling might similarly contribute to DEX resistance in HLH, and that RUX treatment would overcome this phenomenon. Using ex vivo assays, a murine model of HLH, and primary patient samples, we demonstrate that the hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative DEX resistance. Upon exposure to RUX, this apoptotic potential is restored, thereby sensitizing CD8 T cells to DEX-induced apoptosis in vitro and significantly reducing tissue immunopathology and HLH disease manifestations in vivo. Our findings provide rationale for combining DEX and RUX to enhance the lymphotoxic effects of DEX and thus improve the outcomes for patients with HLH and related CSS.