Immunomodulatory effects of pevonedistat, a NEDD8-activating enzyme inhibitor, in chronic lymphocytic leukemia-derived T cells.
Immunomodulatory effects of pevonedistat, a NEDD8-activating enzyme inhibitor, in chronic lymphocytic leukemia-derived T cells.
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DOI：
10.1038/s41375-020-0794-0
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发表时间：
2021-01
期刊：
影响因子：
11.4
通讯作者：
Danilov AV
中科院分区：
文献类型：
--
作者：
Best S;Lam V;Liu T;Bruss N;Kittai A;Danilova OV;Murray S;Berger A;Pennock ND;Lind EF;Danilov AV
用于治疗淋巴恶性肿瘤的新型靶向药物，例如 B 细胞受体相关激酶抑制剂，被认为具有复杂的免疫介导作用。 NEDD8 激活酶 (NAE) 已被确定为慢性淋巴细胞白血病 (CLL) 和非霍奇金淋巴瘤的可治疗靶点。我们和其他人已经证明，pevonedistat (TAK-924) 是一种 NAE 的小分子抑制剂，可以消除恶性 B 细胞中的 NF-κB 信号传导。然而，NF-κB 通路活性在免疫反应中不可或缺，并且 CLL 患者的 T 细胞功能发生改变。使用来自 CLL 患者的 T 细胞，我们证明虽然靶向 NAE 导致 NF-κB 调节基因的显着差异表达和 T 细胞激活过程中白细胞介素 (IL)-2 信号的下调，但 T 细胞逃避凋亡。同时，NAE 抑制在体外有利于调节 T 细胞的极化，减少 Treg 分化并转向 TH1 表型，同时增加干扰素 γ 的产生。这些发现在免疫活性小鼠模型中得到了体内重现。在洗脱实验中，T 细胞暴露于 pevonedistat，根据其人体药代动力学特征，恢复 NAE 活性，并维持其对 T 细胞受体刺激和细胞毒性潜力的反应。我们的数据揭示了 CLL 和淋巴恶性肿瘤中靶向 neddylation 的潜在免疫影响。
Novel targeted agents used in therapy of lymphoid malignancies, such as inhibitors of B-cell receptor-associated kinases, are recognized to have complex immune-mediated effects. NEDD8-activating enzyme (NAE) has been identified as a tractable target in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. We and others have shown that pevonedistat (TAK-924), a small-molecule inhibitor of NAE, abrogates NF-κB signaling in malignant B cells. However, NF-κB pathway activity is indispensable in immune response, and T-cell function is altered in patients with CLL. Using T cells derived from patients with CLL, we demonstrate that although targeting NAE results in markedly differential expression of NF-κB-regulated genes and downregulation of interleukin (IL)-2 signaling during T-cell activation, T cells evade apoptosis. Meanwhile, NAE inhibition favorably modulates polarization of T cells in vitro, with decreased Treg differentiation and a shift toward TH1 phenotype, accompanied by increased interferon-γ production. These findings were recapitulated in vivo in immunocompetent mouse models. T cells exposed to pevonedistat in washout experiments, informed by its human pharmacokinetic profile, recover NAE activity, and maintain their response to T-cell receptor stimulation and cytotoxic potential. Our data shed light on the potential immune implications of targeting neddylation in CLL and lymphoid malignancies.
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影响因子：
8.8
作者：
Fan MY;Low JS;Tanimine N;Finn KK;Priyadharshini B;Germana SK;Kaech SM;Turka LA
通讯作者：
Turka LA
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
DOI：
10.1084/jem.169.1.59
发表时间：
1989-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Heinzel FP;Sadick MD;Holaday BJ;Coffman RL;Locksley RM
通讯作者：
Locksley RM
影响因子：
20.3
作者：
Lampson, Benjamin L.;Kasar, Siddha N.;Brown, Jennifer R.
通讯作者：
Brown, Jennifer R.
影响因子：
64.5
作者：
Dang EV;Barbi J;Yang HY;Jinasena D;Yu H;Zheng Y;Bordman Z;Fu J;Kim Y;Yen HR;Luo W;Zeller K;Shimoda L;Topalian SL;Semenza GL;Dang CV;Pardoll DM;Pan F
通讯作者：
Pan F