以p97-Npl4相互作用为靶点，抑制肿瘤Treg细胞发育以增强肿瘤免疫力

IF 27.7 1区医学 Q1 IMMUNOLOGY

Nature Immunology Pub Date : 2024-08-06 DOI:10.1038/s41590-024-01912-y

Pingping Nie, Zhifa Cao, Ruixian Yu, Chao Dong, Weihong Zhang, Yan Meng, Hui Zhang, Yu Pan, Zhenzhu Tong, Xiaoya Jiang, Shilong Wang, Mengwen Zhu, Yi Han, Wenjia Wang, Yiming Zhang, Lijie Tan, Chuanchuan Li, Yuanzhi Xu, Liwei An, Bin Li, Shi Jiao, Zhaocai Zhou

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引用次数: 0

摘要

靶向肿瘤浸润调节性T细胞（TI-Treg）是一种潜在的癌症治疗策略。ATP 酶 p97 与辅助因子（如 Npl4）的复合物已被研究为抗肿瘤药物靶点；然而，p97 在免疫细胞或免疫疗法中是否具有功能尚不清楚。在这里，我们发现噻唑溴铵是 p97 和 Npl4 相互作用的抑制剂，而且 p97-Npl4 复合物在 TI-Treg 细胞中具有关键功能。溴化芍药可增强抗肿瘤免疫力，但不会影响外周 Treg 细胞的稳态。p97-Npl4复合物将Stat3与E3连接酶PDLIM2和PDLIM5连接起来，从而促进Stat3的降解，使TI-Treg细胞得以发育。总之，这项研究显示了p97-Npl4复合物在控制肿瘤中Treg-TH17细胞平衡方面的重要作用，并确定了免疫疗法的可能靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Targeting p97–Npl4 interaction inhibits tumor Treg cell development to enhance tumor immunity

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Targeting p97–Npl4 interaction inhibits tumor Treg cell development to enhance tumor immunity

Targeting tumor-infiltrating regulatory T (TI-Treg) cells is a potential strategy for cancer therapy. The ATPase p97 in complex with cofactors (such as Npl4) has been investigated as an antitumor drug target; however, it is unclear whether p97 has a function in immune cells or immunotherapy. Here we show that thonzonium bromide is an inhibitor of the interaction of p97 and Npl4 and that this p97–Npl4 complex has a critical function in TI-Treg cells. Thonzonium bromide boosts antitumor immunity without affecting peripheral Treg cell homeostasis. The p97–Npl4 complex bridges Stat3 with E3 ligases PDLIM2 and PDLIM5, thereby promoting Stat3 degradation and enabling TI-Treg cell development. Collectively, this work shows an important role for the p97–Npl4 complex in controlling Treg–TH17 cell balance in tumors and identifies possible targets for immunotherapy. Tumor-infiltrating regulatory T (TI-Treg) cells help tumor growth by suppressing local immune responses. Here the authors show that thonzonium bromide can help fight tumors by interfering with the interaction of p97 and Npl4, a complex that they show supports TI-Treg cells.

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来源期刊

Nature Immunology 医学-免疫学

CiteScore

40.00

自引率

2.30%

发文量

248

审稿时长

4-8 weeks

期刊介绍： Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.