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 wi...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-04-01
|
| Series: | Journal of the National Cancer Center |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667005424001170 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849729946018119680 |
|---|---|
| author | 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 Zhiyuan Xu Ding Li Xiaoling Liang Gilberto Ka-Kit Leung Aya El Helali Chiming Che Feng-Ming (Spring) Kong |
| author_facet | 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 Zhiyuan Xu Ding Li Xiaoling Liang Gilberto Ka-Kit Leung Aya El Helali Chiming Che Feng-Ming (Spring) Kong |
| author_sort | Weiwei Chen |
| collection | DOAJ |
| description | 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. Conclusion: IDO1 metabolites may play immune-suppressive roles in NSCLC patients with Bramet. |
| format | Article |
| id | doaj-art-2adf2a721eed4bc48b67bc73d436e1c0 |
| institution | DOAJ |
| issn | 2667-0054 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of the National Cancer Center |
| spelling | doaj-art-2adf2a721eed4bc48b67bc73d436e1c02025-08-20T03:09:01ZengElsevierJournal of the National Cancer Center2667-00542025-04-015217919210.1016/j.jncc.2024.12.004Indoleamine 2,3-dioxygenase 1-mediated immune suppressive status is positively associated with brain metastasis in patients with non-small cell lung cancerWeiwei Chen0Li Yang1Victor Ho-fun Lee2Liangliang Xu3Lingyu Ma4Zhenghao Ye5Wanli Xu6Caining Zhao7Danyang Zheng8Karrie Mei-Yee Kiang9Stella Sun10Yuan Qu11Jiandong Zha12Dazhi Pang13Yan Zhang14Zhibing Liang15Wenchu Lin16Jinliang Zhang17Jitian Zhang18Min Luo19Zhiyuan Xu20Ding Li21Xiaoling Liang22Gilberto Ka-Kit Leung23Aya El Helali24Chiming Che25 Feng-Ming (Spring) Kong26Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, ChinaDepartment of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, ChinaDepartment of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaKey Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Surgery, The University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Pathology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Pathology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, ChinaDepartment of Surgery, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, ChinaDepartment of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, ChinaDepartment of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong, ChinaDepartment of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China; Department of Clinical Oncology, University of Hong Kong-Shenzhen Hospital, Shenzhen, China; Corresponding author.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. Conclusion: IDO1 metabolites may play immune-suppressive roles in NSCLC patients with Bramet.http://www.sciencedirect.com/science/article/pii/S2667005424001170Indoleamine 2,3-dioxygenaseBrain metastasisImmunosuppressive biomarkerNon-small cell lung cancer |
| spellingShingle | 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 Zhiyuan Xu Ding Li Xiaoling Liang Gilberto Ka-Kit Leung Aya El Helali Chiming Che Feng-Ming (Spring) Kong Indoleamine 2,3-dioxygenase 1-mediated immune suppressive status is positively associated with brain metastasis in patients with non-small cell lung cancer Journal of the National Cancer Center Indoleamine 2,3-dioxygenase Brain metastasis Immunosuppressive biomarker Non-small cell lung cancer |
| title | Indoleamine 2,3-dioxygenase 1-mediated immune suppressive status is positively associated with brain metastasis in patients with non-small cell lung cancer |
| title_full | Indoleamine 2,3-dioxygenase 1-mediated immune suppressive status is positively associated with brain metastasis in patients with non-small cell lung cancer |
| title_fullStr | Indoleamine 2,3-dioxygenase 1-mediated immune suppressive status is positively associated with brain metastasis in patients with non-small cell lung cancer |
| title_full_unstemmed | Indoleamine 2,3-dioxygenase 1-mediated immune suppressive status is positively associated with brain metastasis in patients with non-small cell lung cancer |
| title_short | Indoleamine 2,3-dioxygenase 1-mediated immune suppressive status is positively associated with brain metastasis in patients with non-small cell lung cancer |
| title_sort | indoleamine 2 3 dioxygenase 1 mediated immune suppressive status is positively associated with brain metastasis in patients with non small cell lung cancer |
| topic | Indoleamine 2,3-dioxygenase Brain metastasis Immunosuppressive biomarker Non-small cell lung cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2667005424001170 |
| work_keys_str_mv | AT weiweichen indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT liyang indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT victorhofunlee indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT liangliangxu indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT lingyuma indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT zhenghaoye indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT wanlixu indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT cainingzhao indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT danyangzheng indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT karriemeiyeekiang indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT stellasun indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT yuanqu indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT jiandongzha indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT dazhipang indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT yanzhang indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT zhibingliang indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT wenchulin indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT jinliangzhang indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT jitianzhang indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT minluo indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT zhiyuanxu indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT dingli indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT xiaolingliang indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT gilbertokakitleung indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT ayaelhelali indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT chimingche indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer AT fengmingspringkong indoleamine23dioxygenase1mediatedimmunesuppressivestatusispositivelyassociatedwithbrainmetastasisinpatientswithnonsmallcelllungcancer |