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

  • Nat Commun. 2022 Jun 14;13(1):3419. doi: 10.1038/s41467-022-31141-6.
Yingying Shen   #  1 ,  Chaojie Lu   #  1 ,  Zhengbo Song   #  2 ,  Chenxiao Qiao   #  1 ,  Jiaoli Wang  3  4 ,  Jinbiao Chen  5 ,  Chengyan Zhang  1 ,  Xianchang Zeng  1 ,  Zeyu Ma  1 ,  Tao Chen  6 ,  Xu Li  7 ,  Aifu Lin  8 ,  Jufeng Guo  9 ,  Jianli Wang  10  11 ,  Zhijian Cai  12
Affiliations
  • 1. Institute of Immunology, and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
  • 2. Department of Medical Oncology, Zhejiang Cancer Hospital, 310022, Hangzhou, China.
  • 3. Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 310006, Hangzhou, China.
  • 4. Zhejiang University Cancer Centre, 310006, Hangzhou, China.
  • 5. Department of Oncology, Hangzhou Xixi Hospital, 310023, Hangzhou, China.
  • 6. Department of Orthopedics, Musculoskeletal Tumor Center, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China.
  • 7. School of Life Science, Westlake University, 310024, Hangzhou, China.
  • 8. College of Life Sciences, Zhejiang University, 310058, Hangzhou, China.
  • 9. Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 310006, Hangzhou, China.
  • 10. Institute of Immunology, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China. [email protected].
  • 11. Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, 310006, Hangzhou, China. [email protected].
  • 12. Institute of Immunology, and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 35701426 DOI: 10.1038/s41467-022-31141-6
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.

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