1. YKL-40 derived from infiltrating macrophages cooperates with GDF15 to establish an immune suppressive microenvironment in gallbladder cancer.
- Author
-
Wang, Ziyi, Wang, Shijia, Jia, Ziheng, Hu, Yunping, Cao, Dongyan, Yang, Mingjie, Liu, Liguo, Gao, Li, Qiu, Shimei, Yan, Weikang, Li, Yiming, Luo, Jing, Geng, Yajun, Zhang, Jingyun, Li, Zhizhen, Wang, Xuan, Li, Maolan, Shao, Rong, and Liu, Yingbin
- Subjects
- *
GALLBLADDER cancer , *GROWTH differentiation factors , *TUMOR microenvironment , *MACROPHAGES , *T cells - Abstract
Despite of the high lethality of gallbladder cancer (GBC), little is known regarding molecular regulation of the tumor immunosuppressive microenvironment. Here, we determined tumor expression levels of YKL-40 and the molecular mechanisms by which YKL-40 regulates escape of anti-tumor immune surveillance. We found that elevated expression levels of YKL-40 in plasma and tissue were correlated with tumor size, stage IV and lymph node metastasis. Single cell transcriptome analysis revealed that YKL-40 was predominantly derived from M2-like subtype of infiltrating macrophages. Blockade of M2–like macrophage differentiation of THP-1 cells with YKL-40 shRNA resulted in reprogramming to M1-like macrophages and restricting tumor development. YKL-40 induced tumor cell expression and secretion of growth differentiation factor 15 (GDF15), thus coordinating to promote PD-L1 expression mediated by PI3K, AKT and/or Erk activation. Interestingly, extracellular GDF15 inhibited intracellular expression of GDF15 that suppressed PD-L1 expression. Thus, YKL-40 disrupted the balance of pro- and anti-PD-L1 regulation to enhance expression of PD-L1 and inhibition of T cell cytotoxicity, leading to tumor immune evasion. The data suggest that YKL-40 and GDF15 could serve as diagnostic biomarkers and immunotherapeutic targets for GBC. • Increased YKL-40 in plasma were correlated with tissue expression of YKL-40 and GBC progression. • Blockade of YKL-40 in M2-like macrophages resulted in M1-like macrophage reprogramming. • YKL-40 promoted GDF15 secretion, which in turn inhibited intracellular GDF15 function that suppressed PD-L1 expression. • YKL-40 and GDF15 induced PD-L1 expression and abrogated cytotoxicity of infiltrating CD8+ T lymphocytes. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF