Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation.
Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation.
复制标题
熊去氧胆酸通过诱导 CHIP 介导的 TGF-β 降解来减少抗肿瘤免疫抑制
DOI：
10.1038/s41467-022-31141-6
复制
发表时间：
2022-06-14
影响因子：
16.6
通讯作者：
Cai, Zhijian
中科院分区：
文献类型：
--
作者：
Shen, Yingying;Lu, Chaojie;Song, Zhengbo;Qiao, Chenxiao;Wang, Jiaoli;Chen, Jinbiao;Zhang, Chengyan;Zeng, Xianchang;Ma, Zeyu;Chen, Tao;Li, Xu;Lin, Aifu;Guo, Jufeng;Wang, Jianli;Cai, Zhijian
TGF-β对于诱导全身性肿瘤免疫抑制至关重要；因此，阻断TGF-β可以大大增强抗肿瘤免疫力。然而，目前尚无有效的TGF-β抑制剂应用于临床。在这里，我们证明临床批准的化合物熊去氧胆酸（UDCA）通过降解TGF-β，通过抑制荷瘤小鼠的Treg细胞分化和活化来增强抗肿瘤免疫。此外，UDCA与抗PD-1协同作用，增强荷瘤小鼠的抗肿瘤免疫力和肿瘤特异性免疫记忆。 UDCA 通过 TGR5-cAMP-PKA 轴在 T282 位点磷酸化 TGF-β，导致 TGF-β 与 Hsc70 相互作用蛋白 (CHIP) 羧基末端的结合增加。然后，CHIP 在 K315 位点泛素化 TGF-β，启动 p62 依赖性自噬分选以及随后的 TGF-β 降解。值得注意的是，回顾性分析结果表明，抗PD-1或抗PD-L1与UDCA联合治疗对肿瘤患者的疗效优于单独使用抗PD-1或抗PD-L1。因此，我们的结果显示了 TGF-β 调节的机制，并暗示 UDCA 作为潜在的 TGF-β 抑制剂来增强抗肿瘤免疫。 TGF-β可以增强Treg细胞功能并降低抗肿瘤免疫力。作者在此表明，UDCA 是一种潜在的介质，可以降低 TGF-β 活性并促进小鼠的抗肿瘤免疫反应，并且可以与其他检查点抑制剂相结合。
TGF-β is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-β can greatly enhance antitumor immunity. However, there are still no effective TGF-β inhibitors in clinical use. Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-β, enhances antitumor immunity through restraining Treg cell differentiation and activation in tumor-bearing mice. Furthermore, UDCA synergizes with anti-PD-1 to enhance antitumor immunity and tumor-specific immune memory in tumor-bearing mice. UDCA phosphorylates TGF-β at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-β to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-β at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-β. Notably, results of retrospective analysis shows that combination therapy with anti-PD-1 or anti-PD-L1 and UDCA has better efficacy in tumor patients than anti-PD-1 or anti-PD-L1 alone. Thus, our results show a mechanism for TGF-β regulation and implicate UDCA as a potential TGF-β inhibitor to enhance antitumor immunity. TGF-β can function to increase Treg cell function and reduce anti-tumour immunity. Here the authors show that UDCA is a potential mediator that can reduce TGF-β activity and promote anti-tumour immune responses in mice and can be additive to other checkpoint inhibitors.
登录
查看更多内容
DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
影响因子：
10.5
作者：
Aragon, Eric;Goerner, Nina;Macias, Maria J.
通讯作者：
Macias, Maria J.
影响因子：
4.1
作者：
Kuratomi, G;Komuro, A;Imamura, T
通讯作者：
Imamura, T
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM