1. Academic Validation
  2. 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.
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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