尽管胆囊癌（GBC）的致死率很高，但关于肿瘤免疫抑制微环境的分子调节仍知之甚少。在这里，我们确定了YKL-40的肿瘤表达水平和YKL-40调节肿瘤逃避抗肿瘤免疫监视的分子机制。我们发现，在血浆和组织中，YKL-40的表达水平升高与肿瘤大小、Ⅳ期和淋巴结转移相关。单细胞转录组分析表明，YKL-40主要来自浸润性巨噬细胞的M2样亚型。使用YKL-40 shRNA阻断THP-1细胞的M2样巨噬细胞分化可导致转化为M1样巨噬细胞并限制肿瘤发展。YKL-40诱导肿瘤细胞表达和分泌生长分化因子15（GDF15），从而协调促进PI3K、AKT和/或Erk激活介导的PD-L1表达。有趣的是，胞外GDF15抑制了抑制PD-L1表达的细胞内GDF15表达。因此，YKL-40破坏了促进和抑制PD-L1调节的平衡，增强了PD-L1表达和T细胞细胞毒作用的抑制，从而导致肿瘤免疫逃避。数据表明，YKL-40和GDF15可作为GBC的诊断生物标志物和免疫治疗靶点。版权所有 © 2023 Elsevier B.V. 发布。

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.Copyright © 2023. Published by Elsevier B.V.