2. Academic Validation
  3. L-kynurenine induces NK cell loss in gastric cancer microenvironment via promoting ferroptosis

L-kynurenine induces NK cell loss in gastric cancer microenvironment via promoting ferroptosis

  • J Exp Clin Cancer Res. 2023 Mar 1;42(1):52. doi: 10.1186/s13046-023-02629-w.
Jian-Xin Cui # 1,  Xian-Hui Xu # 2,  Tao He 3,  Jia-Jia Liu 3,  Tian-Yu Xie 1,  Wen Tian 4,  Jun-Yan Liu 5
Affiliations

Affiliations

  • 1 Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
  • 2 Department of Emergency, No. 971 Hospital of PLAN, Qingdao, 266071, Shandong Province, China.
  • 3 Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 4 Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China. [email protected].
  • 5 Department of General Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China. [email protected].
  • # Contributed equally.
PMID: 36855135 DOI: 10.1186/s13046-023-02629-w
Abstract

Background: Natural killer (NK) cells play a major role in body's fighting against various types of cancers. Their infiltration in the tumor microenvironment (TME) of gastric Cancer (GC) are significantly decreased, which has been reported as a robust prognostic marker. However, the causes leading to NK cells loss in GC TME remains poorly understood.

Methods: We constructed a non-contact co-culturing system and humanized xenograft tumor mice model to detect the influence of GC microenvironment on NK-92 or primary human NK cells viability by flow cytometry. Then through using the specific inhibitors for different types of cell death and examining the surrogate markers, we confirmed Ferroptosis in NK cells. Inspired by the accidental discoveries, we constructed a NK-92 cell strain with high expression of GPX4 and treated the humanized xenograft tumor mice model with the NK-92 cells.

Results: We found L-KYN, mainly generated through indoleamine 2, 3-dioxygenase (IDO) from GC cells, impaired NK cells viability in TME. Further analysis revealed L-KYN induced Ferroptosis in NK cells via an AHR-independent way. Moreover, we found NK cells with higher GPX4 expression showed resistance to L-KYN induced Ferroptosis. Based on this, we generated GPX4 over-expressed NK-92 cells, and found these cells showed therapeutic potential towards GC.

Conclusions: Our study revealed a novel mechanism to explain the decline of NK cell number in GC TME. Notably, we also developed a potential immunotherapy strategy, which might be beneficial in clinical treatment in the future.

Keywords

Ferroptosis; Gastric cancer; L-kynurenine; NK cell; Tumor microenvironment.

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