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  3. Icariside I - A novel inhibitor of the kynurenine-AhR pathway with potential for cancer therapy by blocking tumor immune escape

Icariside I - A novel inhibitor of the kynurenine-AhR pathway with potential for cancer therapy by blocking tumor immune escape

  • Biomed Pharmacother. 2022 Sep:153:113387. doi: 10.1016/j.biopha.2022.113387.
Gui Chen 1,  Jiajun Huang 2,  Hehua Lei 3,  Fang Wu 1,  Chuan Chen 1,  Yuchen Song 1,  Zheng Cao 1,  Ce Zhang 1,  Cui Zhang 1,  Yuxi Ma 4,  Mingtao Huang 5,  Jinlin Zhou 6,  Yujing Lu 7,  Yanxia Zhao 8,  Limin Zhang 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, CAS, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Golden Health (Guangdong) Biotechnology Co., Ltd, Foshan 528225, China; School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China.
  • 3 State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, CAS, Wuhan 430071, China.
  • 4 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 5 School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China.
  • 6 Golden Health (Guangdong) Biotechnology Co., Ltd, Foshan 528225, China.
  • 7 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China.
  • 8 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: sophia7781@126.com.
  • 9 State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy of Precision Measurement Science and Technology, CAS, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: zhanglm@wipm.ac.cn.
PMID: 35834991 DOI: 10.1016/j.biopha.2022.113387
Abstract

Background: Although therapeutic antibodies against immune checkpoints such as PD-1/PD-L1 have achieved unprecedented success in clinical tumor patients, there are still many patients who are ineffective or have limited responses to immune checkpoint blockade (ICB). Discovery of novel strategies for Cancer Immunotherapy including natural small molecules is needed.

Methods: Owing to its extremely low content in Epimedium genus, we firstly constructed a microbial cell factory to enzymatically biosynthesize icariside I, a natural flavonoid monosaccharide from Herbal Epimedium. Using a combination of targeted MS-based metabolomics, flow cytometric analysis, and biological assays, the therapeutic potentials of icariside I were subsequently investigated in vivo and in vitro.

Results: We find that icariside I markedly downregulates a series of intermediate metabolites such as kynurenine, kynurenic acid and xanthurenic acid and corresponding key Enzymes involved in kynurenine-AhR pathway in both tumor cells and tumor-bearing mice. In vivo, oral administration of icariside I downregulates SLC7A8 and PAT4 transporters and AhR, thus inhibiting nuclear PD-1 in CTLs. Moreover, icariside I significantly upregulates CD8 + T cells in both peripheral blood and tumor tissues of tumor-bearing mice. Consequently, interferon-γ (IFN-γ) secreted by CD8 + T cells suppresses tumor growth through activation of JAK1-STAT1 signaling, thus inducing tumor cell Apoptosis.

Conclusions: These results suggest that icariside I could be an effective small molecule drug for tumor immunotherapy by blocking kynurenine-AhR pathway and tumor immune escape.

Keywords

Icariside I; Kyn-AhR pathway; PD-1; Tumor immune escape; Tumor immunotherapy.

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