Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways
Joint Authors
O’Dwyer, Michael E.
Zhang, Dan
Teng, Rui
Wang, Yanmeng
Lv, Nan
Williamson, Ramone A.
Lei, Lei
Chen, Ping
Lei, Li
Wang, Baiyan
Fu, Jiaqi
Liu, Xuna
He, Aili
Hu, Jinsong
Source
Journal of Immunology Research
Issue
Vol. 2020, Issue 2020 (31 Dec. 2020), pp.1-14, 14 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2020-06-19
Country of Publication
Egypt
No. of Pages
14
Main Subjects
Abstract EN
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.
American Psychological Association (APA)
Teng, Rui& Wang, Yanmeng& Lv, Nan& Zhang, Dan& Williamson, Ramone A.& Lei, Lei…[et al.]. 2020. Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways. Journal of Immunology Research،Vol. 2020, no. 2020, pp.1-14.
https://search.emarefa.net/detail/BIM-1187213
Modern Language Association (MLA)
Teng, Rui…[et al.]. Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways. Journal of Immunology Research No. 2020 (2020), pp.1-14.
https://search.emarefa.net/detail/BIM-1187213
American Medical Association (AMA)
Teng, Rui& Wang, Yanmeng& Lv, Nan& Zhang, Dan& Williamson, Ramone A.& Lei, Lei…[et al.]. Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways. Journal of Immunology Research. 2020. Vol. 2020, no. 2020, pp.1-14.
https://search.emarefa.net/detail/BIM-1187213
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1187213