Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function
Complement receptor 3 (CR3) is expressed abundantly on natural killer (NK) cells; however, whether it plays roles in NK cell-dependent tumor surveillance is largely unknown. Here, we show that CR3 is an important negative regulator of NK cell function, which has negative impact on tumor surveillance...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01602/full |
| _version_ | 1818561839571664896 |
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| author | Cheng-Fei Liu Xiao-Yun Min Naiyin Wang Jia-Xing Wang Ning Ma Xia Dong Bing Zhang Weiju Wu Zong-Fang Li Zong-Fang Li Wuding Zhou Ke Li Ke Li |
| author_facet | Cheng-Fei Liu Xiao-Yun Min Naiyin Wang Jia-Xing Wang Ning Ma Xia Dong Bing Zhang Weiju Wu Zong-Fang Li Zong-Fang Li Wuding Zhou Ke Li Ke Li |
| author_sort | Cheng-Fei Liu |
| collection | DOAJ |
| description | Complement receptor 3 (CR3) is expressed abundantly on natural killer (NK) cells; however, whether it plays roles in NK cell-dependent tumor surveillance is largely unknown. Here, we show that CR3 is an important negative regulator of NK cell function, which has negative impact on tumor surveillance. Mice deficient in CR3 (CD11b−/− mice) exhibited a more activated NK phenotype and had enhanced NK-dependent tumor killing. In a B16-luc melanoma-induced lung tumor growth and metastasis model, mice deficient in CR3 had reduced tumor growth and metastases, compared with WT mice. In addition, adaptive transfer of NK cells lacking CR3 (into NK-deficient mice) mediated more efficient suppression of tumor growth and metastases, compared with the transfer of CR3 sufficient NK cells, suggesting that CR3 can impair tumor surveillance through suppression of NK cell function. In vitro analyses showed that engagement of CR3 with iC3b (classical CR3 ligand) on NK cells negatively regulated NK cell activity and effector functions (i.e. direct tumor cell killing, antibody-dependent NK-mediated tumor killing). Cell signaling analyses showed that iC3b stimulation caused activation of Src homology 2 domain-containing inositol-5-phosphatase-1 (SHIP-1) and JNK, and suppression of ERK in NK cells, supporting that iC3b mediates negative regulation of NK cell function through its effects on SHIP-1, JNK, and ERK signal transduction pathways. Thus, our findings demonstrate a previously unknown role for CR3 in dysregulation of NK-dependent tumor surveillance and suggest that the iC3b/CR3 signaling is a critical negative regulator of NK cell function and may represent a new target for preserving NK cell function in cancer patients and improving NK cell-based therapy. |
| first_indexed | 2024-12-14T00:55:58Z |
| format | Article |
| id | doaj.art-599d07be48b04185936b69d782f833ca |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T00:55:58Z |
| publishDate | 2017-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-599d07be48b04185936b69d782f833ca2022-12-21T23:23:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-11-01810.3389/fimmu.2017.01602314438Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell FunctionCheng-Fei Liu0Xiao-Yun Min1Naiyin Wang2Jia-Xing Wang3Ning Ma4Xia Dong5Bing Zhang6Weiju Wu7Zong-Fang Li8Zong-Fang Li9Wuding Zhou10Ke Li11Ke Li12Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, ChinaCore Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, ChinaMedical Research Council (MRC) Centre for Transplantation, King’s College London, Guy’s Hospital, London, United KingdomCore Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, ChinaCore Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, ChinaMedical Research Council (MRC) Centre for Transplantation, King’s College London, Guy’s Hospital, London, United KingdomCore Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, ChinaMedical Research Council (MRC) Centre for Transplantation, King’s College London, Guy’s Hospital, London, United KingdomNational Local Joint Engineering Research Centre of Biodiagnostics and Biotherapy, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, ChinaShaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, Xi’an, ChinaMedical Research Council (MRC) Centre for Transplantation, King’s College London, Guy’s Hospital, London, United KingdomCore Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, ChinaNational Local Joint Engineering Research Centre of Biodiagnostics and Biotherapy, The Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, ChinaComplement receptor 3 (CR3) is expressed abundantly on natural killer (NK) cells; however, whether it plays roles in NK cell-dependent tumor surveillance is largely unknown. Here, we show that CR3 is an important negative regulator of NK cell function, which has negative impact on tumor surveillance. Mice deficient in CR3 (CD11b−/− mice) exhibited a more activated NK phenotype and had enhanced NK-dependent tumor killing. In a B16-luc melanoma-induced lung tumor growth and metastasis model, mice deficient in CR3 had reduced tumor growth and metastases, compared with WT mice. In addition, adaptive transfer of NK cells lacking CR3 (into NK-deficient mice) mediated more efficient suppression of tumor growth and metastases, compared with the transfer of CR3 sufficient NK cells, suggesting that CR3 can impair tumor surveillance through suppression of NK cell function. In vitro analyses showed that engagement of CR3 with iC3b (classical CR3 ligand) on NK cells negatively regulated NK cell activity and effector functions (i.e. direct tumor cell killing, antibody-dependent NK-mediated tumor killing). Cell signaling analyses showed that iC3b stimulation caused activation of Src homology 2 domain-containing inositol-5-phosphatase-1 (SHIP-1) and JNK, and suppression of ERK in NK cells, supporting that iC3b mediates negative regulation of NK cell function through its effects on SHIP-1, JNK, and ERK signal transduction pathways. Thus, our findings demonstrate a previously unknown role for CR3 in dysregulation of NK-dependent tumor surveillance and suggest that the iC3b/CR3 signaling is a critical negative regulator of NK cell function and may represent a new target for preserving NK cell function in cancer patients and improving NK cell-based therapy.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01602/fullcomplement receptor 3MelanomaiC3bnatural killer cell functiontumor surveillance |
| spellingShingle | Cheng-Fei Liu Xiao-Yun Min Naiyin Wang Jia-Xing Wang Ning Ma Xia Dong Bing Zhang Weiju Wu Zong-Fang Li Zong-Fang Li Wuding Zhou Ke Li Ke Li Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function Frontiers in Immunology complement receptor 3 Melanoma iC3b natural killer cell function tumor surveillance |
| title | Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function |
| title_full | Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function |
| title_fullStr | Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function |
| title_full_unstemmed | Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function |
| title_short | Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function |
| title_sort | complement receptor 3 has negative impact on tumor surveillance through suppression of natural killer cell function |
| topic | complement receptor 3 Melanoma iC3b natural killer cell function tumor surveillance |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01602/full |
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