Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways
Natural killer (NK) cells are innate immune effectors with potent antitumor activity. However, tumor cells can create an immunosuppressive microenvironment to escape immune surveillance. Although accumulating evidence indicates that microenvironmental hypoxia plays an important role in favoring tumo...
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| Format: | Article |
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Wiley
2020-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2020/4598476 |
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| author | Rui Teng Yanmeng Wang Nan Lv Dan Zhang Ramone A. Williamson Lei Lei Ping Chen Li Lei Baiyan Wang Jiaqi Fu Xuna Liu Aili He Michael O’Dwyer Jinsong Hu |
| author_facet | Rui Teng Yanmeng Wang Nan Lv Dan Zhang Ramone A. Williamson Lei Lei Ping Chen Li Lei Baiyan Wang Jiaqi Fu Xuna Liu Aili He Michael O’Dwyer Jinsong Hu |
| author_sort | Rui Teng |
| collection | DOAJ |
| description | Natural killer (NK) cells are innate immune effectors with potent antitumor activity. However, tumor cells can create an immunosuppressive microenvironment to escape immune surveillance. Although accumulating evidence indicates that microenvironmental hypoxia plays an important role in favoring tumor development and immune evasion, it remains unclear by what means hypoxia directly impairs NK cell antitumor activity. In this study, we confirmed that hypoxic NK cells showed significantly lower cytotoxicity against tumor cells. Consistent with this finding, we found that the reduction in NK cell cytotoxicity resulting from hypoxia correlated to the lower expression of granzyme B, IFN-γ, and degranulation marker CD107a, as well as activating receptors including NKp30, NKp46, and NKG2D expressed on the surface of NK cells. More importantly, we further demonstrated that a reduction in the phosphorylation levels of ERK and STAT3 secondary to hypoxia was strongly associated with the attenuated NK cell cytotoxicity. Focusing on the mechanism responsible for reduced phosphorylation levels of ERK and STAT3, we reveal that the activation of protein tyrosine phosphatase SHP-1 (Src homology region 2 domain-containing phosphatase-1) following hypoxia might play an essential role in this process. By knocking down SHP-1 or blocking its activity using a specific inhibitor TPI-1, we were able to partially restore NK cell cytotoxicity under hypoxia. Taken together, we demonstrate that hypoxia could impair NK cell cytotoxicity by decreasing the phosphorylation levels of ERK and STAT3 in a SHP-1-dependent manner. Therefore, targeting SHP-1 could provide an approach to enhance NK cell-based tumor immunotherapy. |
| format | Article |
| id | doaj-art-6cb7299ec613484e9f0a7d22b256d4fe |
| institution | OA Journals |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-6cb7299ec613484e9f0a7d22b256d4fe2025-08-20T02:06:44ZengWileyJournal of Immunology Research2314-88612314-71562020-01-01202010.1155/2020/45984764598476Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling PathwaysRui Teng0Yanmeng Wang1Nan Lv2Dan Zhang3Ramone A. Williamson4Lei Lei5Ping Chen6Li Lei7Baiyan Wang8Jiaqi Fu9Xuna Liu10Aili He11Michael O’Dwyer12Jinsong Hu13Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, 98 Xi Wu Road, Xi'an, 710004 Shaanxi, ChinaDepartment of Cell Biology and Genetics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, 710061 Shaanxi, ChinaDepartment of Cell Biology and Genetics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, 710061 Shaanxi, ChinaDepartment of Cell Biology and Genetics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, 710061 Shaanxi, ChinaDepartment of Cell Biology and Genetics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, 710061 Shaanxi, ChinaDepartment of Cell Biology and Genetics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, 710061 Shaanxi, ChinaDepartment of Cell Biology and Genetics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, 710061 Shaanxi, ChinaDepartment of Cell Biology and Genetics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, 710061 Shaanxi, ChinaDepartment of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University Health Science Center, 157 Xi Wu Road, Xi'an, 710004 Shaanxi, ChinaDepartment of Cell Biology and Genetics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, 710061 Shaanxi, ChinaDepartment of Cell Biology and Genetics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, 710061 Shaanxi, ChinaDepartment of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University Health Science Center, 157 Xi Wu Road, Xi'an, 710004 Shaanxi, ChinaBiomedical Sciences, National University of Ireland Galway, Galway, IrelandDepartment of Cell Biology and Genetics, Xi’an Jiaotong University Health Science Center, 76 Yanta West Road, Xi’an, 710061 Shaanxi, ChinaNatural killer (NK) cells are innate immune effectors with potent antitumor activity. However, tumor cells can create an immunosuppressive microenvironment to escape immune surveillance. Although accumulating evidence indicates that microenvironmental hypoxia plays an important role in favoring tumor development and immune evasion, it remains unclear by what means hypoxia directly impairs NK cell antitumor activity. In this study, we confirmed that hypoxic NK cells showed significantly lower cytotoxicity against tumor cells. Consistent with this finding, we found that the reduction in NK cell cytotoxicity resulting from hypoxia correlated to the lower expression of granzyme B, IFN-γ, and degranulation marker CD107a, as well as activating receptors including NKp30, NKp46, and NKG2D expressed on the surface of NK cells. More importantly, we further demonstrated that a reduction in the phosphorylation levels of ERK and STAT3 secondary to hypoxia was strongly associated with the attenuated NK cell cytotoxicity. Focusing on the mechanism responsible for reduced phosphorylation levels of ERK and STAT3, we reveal that the activation of protein tyrosine phosphatase SHP-1 (Src homology region 2 domain-containing phosphatase-1) following hypoxia might play an essential role in this process. By knocking down SHP-1 or blocking its activity using a specific inhibitor TPI-1, we were able to partially restore NK cell cytotoxicity under hypoxia. Taken together, we demonstrate that hypoxia could impair NK cell cytotoxicity by decreasing the phosphorylation levels of ERK and STAT3 in a SHP-1-dependent manner. Therefore, targeting SHP-1 could provide an approach to enhance NK cell-based tumor immunotherapy.http://dx.doi.org/10.1155/2020/4598476 |
| spellingShingle | Rui Teng Yanmeng Wang Nan Lv Dan Zhang Ramone A. Williamson Lei Lei Ping Chen Li Lei Baiyan Wang Jiaqi Fu Xuna Liu Aili He Michael O’Dwyer Jinsong Hu Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways Journal of Immunology Research |
| title | Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways |
| title_full | Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways |
| title_fullStr | Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways |
| title_full_unstemmed | Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways |
| title_short | Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways |
| title_sort | hypoxia impairs nk cell cytotoxicity through shp 1 mediated attenuation of stat3 and erk signaling pathways |
| url | http://dx.doi.org/10.1155/2020/4598476 |
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