FasL+PD‐L2+ Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression
Abstract Neutrophils constitute abundant cellular components in human gastric cancer (GC) tissues, but their protumorigenic subset in pathogenesis of GC progression is unclear. Here, it is found that patients with GC show significantly higher neutrophil infiltration in tumors that is regulated by CX...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-02-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202103543 |
| _version_ | 1819278403358949376 |
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| author | Zhi‐Guo Shan Yong‐Liang Zhao Jin‐Yu Zhang Zong‐Bao Yan Ting‐Ting Wang Fang‐Yuan Mao Yong‐Sheng Teng Liu‐Sheng Peng Wan‐Yan Chen Pan Wang Ping Cheng Wen‐Qing Tian Jun Chen Weisan Chen Yuan Zhuang |
| author_facet | Zhi‐Guo Shan Yong‐Liang Zhao Jin‐Yu Zhang Zong‐Bao Yan Ting‐Ting Wang Fang‐Yuan Mao Yong‐Sheng Teng Liu‐Sheng Peng Wan‐Yan Chen Pan Wang Ping Cheng Wen‐Qing Tian Jun Chen Weisan Chen Yuan Zhuang |
| author_sort | Zhi‐Guo Shan |
| collection | DOAJ |
| description | Abstract Neutrophils constitute abundant cellular components in human gastric cancer (GC) tissues, but their protumorigenic subset in pathogenesis of GC progression is unclear. Here, it is found that patients with GC show significantly higher neutrophil infiltration in tumors that is regulated by CXCL12‐CXCR4 chemotaxis. These tumor‐infiltrating neutrophils express high level immunosuppressive molecules FasL and PD‐L2, and this FasL+PD‐L2+ neutrophil subset with a unique phenotype constitutes at least 20% of all neutrophils in advanced GC and predicts poor patient survival. Tumor induces neutrophils to express FasL and PD‐L2 proteins with similar phenotype to those in GC tumors in both time‐dependent and dose‐dependent manners. Mechanistically, Th17 cell‐derived IL‐17A and tumor cell‐derived G‐CSF can significantly induce neutrophil FasL and PD‐L2 expression via activating ERK‐NF‐κB and JAK‐STAT3 signaling pathway, respectively. Importantly, upon over‐expressing FasL and PD‐L2, neutrophils acquire immunosuppressive functions on tumor‐specific CD8+ T‐cells and promote the growth and progression of human GC tumors in vitro and in vivo, which can be reversed by blocking FasL and PD‐L2 on these neutrophils. Thus, the work identifies a novel protumorigenic FasL+PD‐L2+ neutrophil subset in GC and provides new insights for human cancer immunosuppression and anti‐cancer therapies targeting these pathogenic cells. |
| first_indexed | 2024-12-24T00:11:27Z |
| format | Article |
| id | doaj.art-61422758079c4ea3a1bc9e4a6a6ffd29 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-24T00:11:27Z |
| publishDate | 2022-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-61422758079c4ea3a1bc9e4a6a6ffd292022-12-21T17:24:52ZengWileyAdvanced Science2198-38442022-02-0195n/an/a10.1002/advs.202103543FasL+PD‐L2+ Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease ProgressionZhi‐Guo Shan0Yong‐Liang Zhao1Jin‐Yu Zhang2Zong‐Bao Yan3Ting‐Ting Wang4Fang‐Yuan Mao5Yong‐Sheng Teng6Liu‐Sheng Peng7Wan‐Yan Chen8Pan Wang9Ping Cheng10Wen‐Qing Tian11Jun Chen12Weisan Chen13Yuan Zhuang14Department of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery Southwest Hospital Third Military Medical University Chongqing 400038 ChinaDepartment of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery Southwest Hospital Third Military Medical University Chongqing 400038 ChinaNational Engineering Research Center of Immunological Products Department of Microbiology and Biochemical Pharmacy College of Pharmacy and Laboratory Medicine Third Military Medical University Chongqing 400038 ChinaDepartment of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery Southwest Hospital Third Military Medical University Chongqing 400038 ChinaChongqing Key Research Laboratory for Drug Metabolism Department of Pharmacology Chongqing Medical University Chongqing 400016 ChinaNational Engineering Research Center of Immunological Products Department of Microbiology and Biochemical Pharmacy College of Pharmacy and Laboratory Medicine Third Military Medical University Chongqing 400038 ChinaNational Engineering Research Center of Immunological Products Department of Microbiology and Biochemical Pharmacy College of Pharmacy and Laboratory Medicine Third Military Medical University Chongqing 400038 ChinaNational Engineering Research Center of Immunological Products Department of Microbiology and Biochemical Pharmacy College of Pharmacy and Laboratory Medicine Third Military Medical University Chongqing 400038 ChinaNational Engineering Research Center of Immunological Products Department of Microbiology and Biochemical Pharmacy College of Pharmacy and Laboratory Medicine Third Military Medical University Chongqing 400038 ChinaNational Engineering Research Center of Immunological Products Department of Microbiology and Biochemical Pharmacy College of Pharmacy and Laboratory Medicine Third Military Medical University Chongqing 400038 ChinaNational Engineering Research Center of Immunological Products Department of Microbiology and Biochemical Pharmacy College of Pharmacy and Laboratory Medicine Third Military Medical University Chongqing 400038 ChinaDepartment of Endocrinology the First Affiliated Hospital of Chongqing Medical University Chongqing 400016 ChinaDepartment of General Surgery and Center of Minimal Invasive Gastrointestinal Surgery Southwest Hospital Third Military Medical University Chongqing 400038 ChinaLa Trobe Institute of Molecular Science La Trobe University Bundoora Victoria 3085 AustraliaDepartment of Gastroenterology the Affiliated Hospital of Southwest Medical University Luzhou Sichuan 646000 ChinaAbstract Neutrophils constitute abundant cellular components in human gastric cancer (GC) tissues, but their protumorigenic subset in pathogenesis of GC progression is unclear. Here, it is found that patients with GC show significantly higher neutrophil infiltration in tumors that is regulated by CXCL12‐CXCR4 chemotaxis. These tumor‐infiltrating neutrophils express high level immunosuppressive molecules FasL and PD‐L2, and this FasL+PD‐L2+ neutrophil subset with a unique phenotype constitutes at least 20% of all neutrophils in advanced GC and predicts poor patient survival. Tumor induces neutrophils to express FasL and PD‐L2 proteins with similar phenotype to those in GC tumors in both time‐dependent and dose‐dependent manners. Mechanistically, Th17 cell‐derived IL‐17A and tumor cell‐derived G‐CSF can significantly induce neutrophil FasL and PD‐L2 expression via activating ERK‐NF‐κB and JAK‐STAT3 signaling pathway, respectively. Importantly, upon over‐expressing FasL and PD‐L2, neutrophils acquire immunosuppressive functions on tumor‐specific CD8+ T‐cells and promote the growth and progression of human GC tumors in vitro and in vivo, which can be reversed by blocking FasL and PD‐L2 on these neutrophils. Thus, the work identifies a novel protumorigenic FasL+PD‐L2+ neutrophil subset in GC and provides new insights for human cancer immunosuppression and anti‐cancer therapies targeting these pathogenic cells.https://doi.org/10.1002/advs.202103543FasLgastric cancerneutrophilsPD‐L2 |
| spellingShingle | Zhi‐Guo Shan Yong‐Liang Zhao Jin‐Yu Zhang Zong‐Bao Yan Ting‐Ting Wang Fang‐Yuan Mao Yong‐Sheng Teng Liu‐Sheng Peng Wan‐Yan Chen Pan Wang Ping Cheng Wen‐Qing Tian Jun Chen Weisan Chen Yuan Zhuang FasL+PD‐L2+ Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression Advanced Science FasL gastric cancer neutrophils PD‐L2 |
| title | FasL+PD‐L2+ Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression |
| title_full | FasL+PD‐L2+ Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression |
| title_fullStr | FasL+PD‐L2+ Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression |
| title_full_unstemmed | FasL+PD‐L2+ Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression |
| title_short | FasL+PD‐L2+ Identifies a Novel Immunosuppressive Neutrophil Population in Human Gastric Cancer That Promotes Disease Progression |
| title_sort | fasl pd l2 identifies a novel immunosuppressive neutrophil population in human gastric cancer that promotes disease progression |
| topic | FasL gastric cancer neutrophils PD‐L2 |
| url | https://doi.org/10.1002/advs.202103543 |
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