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Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia
Leukemia ( IF 12.8 ) Pub Date : 2023-04-08 , DOI: 10.1038/s41375-023-01889-x
Xiaoguang Wang 1 , Canping Chen 2 , Dan Vuong 1 , Sonia Rodriguez-Rodriguez 1 , Vi Lam 1 , Carly Roleder 1 , Jing H Wang 3 , Swetha Kambhampati Thiruvengadam 1 , Allison Berger 4 , Nathan Pennock 5 , Pallawi Torka 6 , Francisco Hernandez-Ilizaliturri 6 , Tanya Siddiqi 1 , Lili Wang 1 , Zheng Xia 2 , Alexey V Danilov 1
Affiliation  

Neddylation is a sequential enzyme-based process which regulates the function of E3 Cullin-RING ligase (CRL) and thus degradation of substrate proteins. Here we show that CD8+ T cells are a direct target for therapeutically relevant anti-lymphoma activity of pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor. Pevonedistat-treated patient-derived CD8+ T cells upregulated TNFα and IFNγ and exhibited enhanced cytotoxicity. Pevonedistat induced CD8+ T-cell inflamed microenvironment and delayed tumor progression in A20 syngeneic lymphoma model. This anti-tumor effect lessened when CD8+ T cells lost the ability to engage tumors through MHC class I interactions, achieved either through CD8+ T-cell depletion or genetic knockout of B2M. Meanwhile, loss of UBE2M in tumor did not alter efficacy of pevonedistat. Concurrent blockade of NAE and PD-1 led to enhanced tumor immune infiltration, T-cell activation and chemokine expression and synergistically restricted tumor growth. shRNA-mediated knockdown of HIF-1α, a CRL substrate, abrogated the in vitro effects of pevonedistat, suggesting that NAE inhibition modulates T-cell function in HIF-1α-dependent manner. scRNA-Seq-based clinical analyses in lymphoma patients receiving pevonedistat therapy demonstrated upregulation of interferon response signatures in immune cells. Thus, targeting NAE enhances the inflammatory T-cell state, providing rationale for checkpoint blockade-based combination therapy.



中文翻译:


Nedd8 激活酶的药理学靶向可恢复淋巴瘤中的 T 细胞反应



Neddylation 是一种基于酶的连续过程,可调节 E3 Cullin-RING 连接酶 (CRL) 的功能,从而降解底物蛋白。在这里,我们表明 CD8 + T 细胞是 Pevonedistat(一种 Nedd8 激活酶 (NAE) 抑制剂)治疗相关抗淋巴瘤活性的直接靶标。Pevonedistat 处理的患者来源的 CD8 + T 细胞上调 TNFα 和 IFNγ 并表现出增强的细胞毒性。Pevonedistat 在 A20 同基因淋巴瘤模型中诱导 CD8+ T 细胞发炎微环境并延缓肿瘤进展。当 CD8+ T 细胞通过 MHC I 类相互作用失去与肿瘤结合的能力时,这种抗肿瘤作用减弱,通过 CD8+ T 细胞耗竭或 B2M 的基因敲除实现。同时,肿瘤中 UBE2M 的缺失不会改变 pevonedistat 的疗效。同时阻断 NAE 和 PD-1 导致肿瘤免疫浸润增强、T 细胞活化和趋化因子表达,协同限制肿瘤生长。shRNA 介导的 CRL 底物 HIF-1α 的敲低消除了 pevonedistat 的体外作用,表明 NAE 抑制以 HIF-1α 依赖性方式调节 T 细胞功能。对接受 pevonedistat 治疗的淋巴瘤患者进行的基于 scRNA-Seq 的临床分析表明,免疫细胞中干扰素反应特征上调。因此,靶向 NAE 可增强炎性 T 细胞状态,为基于检查点阻断的联合治疗提供基本原理。

更新日期:2023-04-09
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