Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.
Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.
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DOI：
10.1038/s41375-023-01889-x
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发表时间：
2023-06
期刊：
影响因子：
11.4
通讯作者：
Danilov, Alexey V.
中科院分区：
文献类型：
--
作者：
Wang, Xiaoguang;Chen, Canping;Vuong, Dan;Rodriguez-Rodriguez, Sonia;Lam, Vi;Roleder, Carly;Wang, Jing H.;Kambhampati, Swetha;Berger, Allison;Pennock, Nathan;Torka, Pallawi;Hernandez-Ilizaliturri, Francisco;Siddiqi, Tanya;Wang, Lili;Xia, Zheng;Danilov, Alexey V.
Neddylation 是一个基于酶的连续过程，可调节 E3 Cullin-RING 连接酶 (CRL) 的功能，从而调节底物蛋白的降解。在这里，我们证明 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 治疗的患者来源的 CD8+ T 细胞上调 TNFα 和 IFNγ，并表现出增强的细胞毒性。在 A20 同基因淋巴瘤模型中，Pevonedistat 诱导 CD8+ T 细胞炎症微环境并延迟肿瘤进展。当 CD8+ T 细胞失去通过 MHC I 类相互作用（通过 CD8+ T 细胞耗竭或 B2M 基因敲除来实现）攻击肿瘤的能力时，这种抗肿瘤作用就会减弱。同时，肿瘤中 UBE2M 的缺失并没有改变 pevonedistat 的疗效。同时阻断 NAE 和 PD-1 可增强肿瘤免疫浸润、T 细胞激活和趋化因子表达，并协同限制肿瘤生长。 shRNA 介导的 CRL 底物 HIF-1α 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 可以增强炎症 T 细胞状态，为基于检查点阻断的联合疗法提供理论依据。
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.
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DOI：
10.4172/1948-5956.1000543
发表时间：
2018
期刊：
Journal of cancer science & therapy
影响因子：
--
作者：
Filippova N;Yang X;An Z;Nabors LB;Pereboeva L
通讯作者：
Pereboeva L
影响因子：
3.4
作者：
Lam, Vi;Best, Scott;Danilov, Alexey V.
通讯作者：
Danilov, Alexey V.
影响因子：
2.9
作者：
Kersh AE;Ng S;Chang YM;Sasaki M;Thomas SN;Kissick HT;Lesinski GB;Kudchadkar RR;Waller EK;Pollack BP
通讯作者：
Pollack BP
影响因子：
4.4
作者：
Gibson, Heather M.;Hedgcock, Carrie J.;Wong, Henry K.
通讯作者：
Wong, Henry K.
影响因子：
50.3
作者：
McGrail, Daniel J.;Garnett, Jeannine;Lin, Shiaw-Yih
通讯作者：
Lin, Shiaw-Yih