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

TGF-? is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-? can greatly enhance antitumor immunity. However, there are still no effective TGF-? inhibitors in clinical use. Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-?, 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-? at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-? to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-? at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-?. 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-? regulation and implicate UDCA as a potential TGF-? inhibitor to enhance antitumor immunity.
Mesh Terms:
Animals, Cell Line, Tumor, Humans, Immunosuppression Therapy, Mice, Neoplasms, Retrospective Studies, Transforming Growth Factor beta, Ursodeoxycholic Acid
Nat Commun
Date: Dec. 14, 2021
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