Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation
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.
https://www.nature.com/articles/s41467-022-31141-6
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Potential TGF-beta Inhibitors
- PPAR gamma and PPAR alpha agonists [35, 36, 37, 38]
- Vitamin D Receptor activation [39], Angiotensin II type 1 receptor antagonism [40]
- Sun/UV [41, 42] (skin cells)
- Klotho (may bind to the TGF-β1 receptor to inhibit TGF-β1 binding) [32].
- Curcumin [43]
- Black Cumin Seed Oil /Thymoquinone [44] (rat model of allergic airway inflammation)
- Andrographis/Andrographolide [45]
- Ursolic acid [46]
- Extra Virgin Olive Oil [47]
- Reishi [48]
- Fucoidan [49]
- Resveratrol [50]
- Apigenin [51]
- Berberine [52]
- Quercetin[53]
- Grape Seed Extract
- Ginkgo [54]
- Astragalus [55, 56]
- Zinc
- Silymarin/Silibinin
- Hesperidin
- Garlic
- Gotu Kola /Asiatic Acid,
- Emodin (found in Fo-Ti, Resveratrol, Rhubarb, Aloe)
- Theanine [57]
- Naringenin
- Ginseng [58]
- Kudzu root/Puerarin
- Angelica S, Hydrangea, Dan Shen, Almond, Cordyceps, Butein, Betulinic acid
- These growth factors inhibited a TGFbeta1 increase in cells: IGF-I, EGF, and Growth Hormone (cellular model) [59]