ReferenceID 6449
Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation
Nat Commun
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 th
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Record Fields
Scalar fields from the final reference record.
- Reference Id
- 6449
- Evidence Id
- 23039
- Core Evidence Id
- 23039
- Source Reference Id
- 6191
- Herb2 Reference Id
- HBREF006988
- Subject Paper Key
- HBIN047610_35701426
- Pubmed Id
- 35701426
- Doi
- 10.1038/s41467-022-31141-6
- Paper Title
- Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation
- Paper 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.
- Journal
- Nat Commun
- Publish Year
- 2022
- Experiment Subject
- mouse; patient
- Experiment Type
- Animal Experiment
- Phenotype Related
- Systemic Tumor; Tumor
- Paper Title Cn
- Paper Title En
- Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation
- Bilingual Status
- semi_complete