USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy.
USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy.
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DOI：
10.1038/s41467-022-29401-6
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发表时间：
2022-03-31
影响因子：
16.6
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Xiong W;Gao X;Zhang T;Jiang B;Hu MM;Bu X;Gao Y;Zhang LZ;Xiao BL;He C;Sun Y;Li H;Shi J;Xiao X;Xiang B;Xie C;Chen G;Zhang H;Wei W;Freeman GJ;Shu HB;Wang H;Zhang J
抗PD-1/PD-L1免疫疗法在多种癌症患者中取得了令人印象深刻的治疗效果。然而，对PD-1/PD-L1阻断剂的中度缓解率（15-25%）或耐药性的下划线分子机制仍不完全清楚。在这里，我们报告说，抑制去泛素化酶，USP 8，通过重塑炎症肿瘤微环境（TME）显着增强抗PD-1/PD-L1免疫治疗的疗效。从机制上讲，USP 8抑制通过提高TRAF 6介导的K63连接的PD-L1泛素化来拮抗K48连接的PD-L1泛素化和降解，从而增加PD-L1蛋白丰度。此外，USP 8抑制还主要通过激活NF-κB信号传导触发先天免疫应答和MHC-I表达。基于这些机制，USP 8抑制剂与PD-1/PD-L1阻断剂的组合显著激活浸润的CD 8 + T细胞以抑制肿瘤生长，并改善几种小鼠肿瘤模型中的存活益处。因此，我们的研究揭示了一种潜在的联合治疗策略，即利用USP 8抑制剂和PD-1/PD-L1阻断剂来增强抗肿瘤疗效。PD-L1翻译后修饰的调控机制尚未完全了解。在本文中，作者表明USP 8通过去除PD-L1的K63连接的泛素化来负调节PD-L1蛋白丰度;而USP 8抑制通过激活NF-κB信号传导增加MHC-I表达并触发抗肿瘤免疫应答。
Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15–25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8+ T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy. The regulatory mechanisms of PD-L1 posttranslational modifications are not completely understood. Here the authors show that USP8 negatively regulates PD-L1 protein abundance by removing the K63-linked ubiquitination of PD-L1; while USP8 inhibition increases MHC-I expression and triggers anti-tumour immune responses through activating NF-κB signalling.
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DOI：
10.1038/nrd.2017.152
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
通讯作者：
Jackson SP
DOI：
10.1038/s41577-019-0218-4
发表时间：
2020-01
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Kalbasi A;Ribas A
通讯作者：
Ribas A
影响因子：
3.3
作者：
Czeminski, Rakefet;Amornphimoltham, Panomwat;Gutkind, J. Silvio
通讯作者：
Gutkind, J. Silvio
影响因子：
8
作者：
Jeong, M.;Lee, E-W;Song, J.
通讯作者：
Song, J.
影响因子：
64.8
作者：
Burr ML;Sparbier CE;Chan YC;Williamson JC;Woods K;Beavis PA;Lam EYN;Henderson MA;Bell CC;Stolzenburg S;Gilan O;Bloor S;Noori T;Morgens DW;Bassik MC;Neeson PJ;Behren A;Darcy PK;Dawson SJ;Voskoboinik I;Trapani JA;Cebon J;Lehner PJ;Dawson MA
通讯作者：
Dawson MA