2. Academic Validation
  3. Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation

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

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. jlwang@zju.edu.cn.
  • 11 Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, 310006, Hangzhou, China. jlwang@zju.edu.cn.
  • 12 Institute of Immunology, and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China. caizj@zju.edu.cn.
  • # 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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