吲哚胺2,3-双加氧酶1介导的免疫抑制状态与非小细胞肺癌患者脑转移呈正相关

IF 9.4 Q1 ONCOLOGY Journal of the National Cancer Center Pub Date : 2025-04-01 Epub Date: 2024-12-15 DOI:10.1016/j.jncc.2024.12.004

Weiwei Chen , Li Yang , Victor Ho-fun Lee , Liangliang Xu , Lingyu Ma , Zhenghao Ye , Wanli Xu , Caining Zhao , Danyang Zheng , Karrie Mei-Yee Kiang , Stella Sun , Yuan Qu , Jiandong Zha , Dazhi Pang , Yan Zhang , Zhibing Liang , Wenchu Lin , Jinliang Zhang , Jitian Zhang , Min Luo , Feng-Ming (Spring) Kong

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引用次数: 0

摘要

犬尿氨酸/色氨酸（K:T）比值测定的吲哚胺2,3-双加氧酶（IDO1）活性与非小细胞肺癌（NSCLC）患者的远处转移和总生存率（OS）有关。在此，我们旨在研究IDO1活性是否与NSCLC脑转移（Bramet）患者的OS相关，以及是否对调节免疫细胞的抗肿瘤功能有负面影响。方法本研究是循环生物标志物前瞻性临床试验的一部分。收集符合条件的参与者的血液或组织，测量犬尿氨酸、色氨酸、免疫细胞亚型、scRNA-seq分析和非靶向代谢组学分析。结果共纳入195例患者。犬尿氨酸与色氨酸（K:T）比值中值为0.18，非小细胞肺癌Bramet患者与非小细胞肺癌Bramet患者的K:T比值中值一致（分别为0.18和0.11）。值得注意的是，学生t检验分析显示，IV期患者的犬尿氨酸浓度明显高于I期患者(2.3 μ M vs 1.7 μ M, P <；0.001)。与脑外转移患者相比，Bramet患者的犬尿氨酸浓度和K:T比值均显著升高(2.7 vs 1.9 μ M, P <；0.001;0.12 vs 0.095, P = 0.028；分别)。单细胞分析进一步证实了IDO1在IV期肿瘤或Bramet病变中的高水平表达，特别是在巨噬细胞中，由CXCL11等趋化因子调节。此外，K:T比值与Bramet患者的Treg细胞百分比和OS有显著相关性（P = 0.039）。犬尿氨酸治疗导致T细胞中免疫抑制分子（包括PD-1）的上调。最后，非靶向代谢组学分析进一步发现，除了IDO1代谢途径外，其他代谢物，如参与磷脂途径的代谢物，也与Bramet有关。结论ido1代谢物可能在Bramet非小细胞肺癌患者中发挥免疫抑制作用。

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Indoleamine 2,3-dioxygenase 1-mediated immune suppressive status is positively associated with brain metastasis in patients with non-small cell lung cancer

Background

Indoleamine 2,3-dioxygenase (IDO1) activity, measured by kynurenine/tryptophan (K:T) ratio, is known for its association with distant metastasis and overall survival (OS) in patients with non-small cell lung cancer (NSCLC). Here, we aimed to examine whether IDO1 activity is correlated with OS in NSCLC patients with brain metastasis (Bramet) and has negative effect on modulating the anti-tumor functions of immune cells.

Methods

This study was a part of a prospective clinical trial in circulating biomarkers. Blood or tissues from eligible participants were collected for measurement of kynurenine, tryptophan, immune cell subtype, scRNA-seq analysis, and untargeted metabolomics analysis.

Results

A total of 195 patients were enrolled. The median kynurenine to tryptophan (K:T) ratio was 0.18, with consistent values observed among patients with NSCLC Bramet and those without (0.18 and 0.11, respectively). Notably, student's t-test analysis revealed significantly higher kynurenine concentrations in stage IV patients compared to those in stage I (2.3 vs 1.7 µM, P < 0.001). In patients with Bramet, both kynurenine concentrations and K:T ratios were significantly elevated in comparison with those of extra-cerebral metastasis (2.7 vs 1.9 µM, P < 0.001; 0.12 vs 0.095, P = 0.028; respectively). Single-cell analysis further validated a high level of IDO1 expression in stage IV tumors or Bramet lesions, particularly in macrophages, regulated by chemokines such as CXCL11. Additionally, K:T ratios exhibited significant associations with Treg cell percentages and OS in patients with Bramet (P = 0.039). Treatment with kynurenine led to the upregulation of immune-suppressive molecules, including PD-1, in T cells. Finally, untargeted metabolomics analysis further identified that, apart from the IDO1 metabolic pathway, other metabolites, such as those involved in phospholipid pathways, were also implicated in Bramet.