Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation

Yingying Shen, Chaojie Lu, Zhengbo Song, Chenxiao Qiao, Jiaoli Wang, Jinbiao Chen, Chengyan Zhang, Xianchang Zeng, Zeyu Ma, Tao Chen, Xu Li, Aifu Lin, Jufeng Guo, Jianli Wang () and Zhijian Cai ()
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Yingying Shen: Zhejiang University School of Medicine
Chaojie Lu: Zhejiang University School of Medicine
Zhengbo Song: Zhejiang Cancer Hospital
Chenxiao Qiao: Zhejiang University School of Medicine
Jiaoli Wang: Zhejiang University School of Medicine
Jinbiao Chen: Hangzhou Xixi Hospital
Chengyan Zhang: Zhejiang University School of Medicine
Xianchang Zeng: Zhejiang University School of Medicine
Zeyu Ma: Zhejiang University School of Medicine
Tao Chen: Zhejiang University School of Medicine
Xu Li: Westlake University
Aifu Lin: Zhejiang University
Jufeng Guo: Zhejiang University School of Medicine
Jianli Wang: Zhejiang University School of Medicine
Zhijian Cai: Zhejiang University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31141-6

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