2. Academic Validation
  3. Activated kynurenine pathway metabolism by YKL-40 establishes an inhibitory immune microenvironment and drives glioblastoma development

Activated kynurenine pathway metabolism by YKL-40 establishes an inhibitory immune microenvironment and drives glioblastoma development

  • Cell Mol Life Sci. 2024 Dec 24;82(1):11. doi: 10.1007/s00018-024-05497-5.
Hui Chen # 1 2,  Xuemei Zhang # 3,  Ziyi Wang 4 5,  Jing Luo 6,  Yingbin Liu 7 8,  Rong Shao 9 10
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
  • 2 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 3 Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
  • 4 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 5 Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 6 Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
  • 7 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. laoniulyb@shsmu.edu.cn.
  • 8 Department of Biliary-Pancreatic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. laoniulyb@shsmu.edu.cn.
  • 9 Shanghai Key Laboratory of Biliary Tract Disease Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. rongshao19981962@163.com.
  • 10 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. rongshao19981962@163.com.
  • # Contributed equally.
PMID: 39718635 DOI: 10.1007/s00018-024-05497-5
Abstract

Background: Glioblastoma (GB) is the stage IV of glioma and mesenchymal GB represents the most common and malignant subtype characterized with elevated expression of a mesenchymal marker YKL-40 and resistance to immune drug therapy. Here, we determined if YKL-40 regulates kynurenine (Kyn) pathway (KP) metabolism that contributes to establishing an immune suppressive microenvironment in GB.

Methods: Tumor cells expressing YKL-40 from GB patients were isolated and activated cellular metabolisms were identified via gene microarray analysis. KP metabolism was determined by LC/MS/MS system. Indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase (TDO2), their regulatory transcription factors AhR and SRF were evaluated using WB. AhR and SRF transactivity was measured by luciferase reporter gene assays with binding motif mutation, while m6A-mediated AhR and SRF mRNA stability was determined in the presence of an METTL3inhibitor. YKL-40 and Kyn-induced tumor cell migration and CD8+ cytotoxic T cell (CTL) Apoptosis were measured in cultured cells. Tumors cells expressing YKL-40 were injected to mouse brains to establish orthotpic tumor models. In GB, YKL-40, IDO1 and TDO2 expression was analyzed for correlation with patient survival.

Results: KP metabolism was activated in YKL-40-expressing tumor cells. YKL-40 divergently regulated IDO1 and TDO2 via induction of AhR and SRF, respectively. mRNA levels of AhR and SRF were stabilized by decreased METTL3 and YTHDF2. YKL-40 and Kyn secreted from tumor cells and infiltrating M2 macrophages cooperated to enhance tumor cell migration and inhibit CTL immunity. In xenografts, tumors expressing YKL-40 displayed the elevated KP metabolism and macrophage infiltration, but decreased CTLs. Treatment with an anti-PD-1 antibody Tislelizumab significantly increased YKL-40+ mouse survival. In GB, YKL-40 was positively correlated with IDO1 expression and both were associated with decreased survival, whereas IDO1 was negatively correlated with TDO2.

Conclusion: YKL-40 upregulates IDO1 or TDO2 to activate KP metabolism, and coordinates with Kyn to establish an inhibitory tumor immune microenvironment, leading to tumor immune evasion.

Keywords

Glioblastoma (GB); Immune evasion; Indoleamine 2,3-dioxygenase 1 (IDO1); METTL3; Tryptophan 2,3-dioxygenase (TDO2); YKL-40 (CHI3L1).

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