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Published on: February 22, 2020
Functional expression of CD73 on human natural killer cells
Andrea M Chambers1, Jiao Wang1, Tram N Dao1
1Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, 47907, USA.
Abstract:
The production of adenosine by CD73 on cancer cells in the tumor microenvironment is a recognized immunosuppressive mechanism contributing to immune evasion in many solid tumors. While NK cells have been purported to overexpress CD73 under certain conditions, this phenomenon has remained elusive and unclear. We have found that while NK cells are able to upregulate expression of CD73 on their surface when exposed to CD73+ cancer cells, this upregulation is not universal, nor is it often substantial. Rather, our data point to the extent of CD73 expression on NK cells to be both cancer-specific and environmentally-driven, and largely limited in intensity. We found that NK cell overexpression of CD73 responds to the level of CD73 on cancer cells and is enhanced in hypoxia. Interestingly, human CD73+ NK cells appear hyperfunctional in vitro compared to CD73- NK cells, suggesting that CD73 expression could be a bystander of NK cell activation. In addition, glioblastoma patient data show that tumor-infiltrating NK cells express CD73 variably, depending on donor, and present lower expression of CD16, alongside patient-specific changes in CEACAM1, CXCR3 and TIM-3, suggesting some functional changes in NK cell responses associated with expression of CD73 on NK cells in vivo. Taken together, our study is the first to show that while NK cells are largely resistant to the upregulation of CD73, CD73 expression is inducible on NK cells in response to CD73 on cancer cells, and these cells are associated with distinct functional signatures.
Insights
Natural killer (NK) cells can upregulate CD73 expression when interacting with cancer cells, influenced by cancer cell CD73 levels and hypoxia. This inducible CD73 expression on NK cells is linked to distinct functional changes, particularly in the tumor microenvironment.
Area of Science:
- Immunology
- Cancer Biology
- Tumor Microenvironment
Background:
- CD73 on cancer cells promotes immune evasion by producing adenosine, an immunosuppressive molecule.
- The role and extent of CD73 expression on natural killer (NK) cells remain unclear.
- Previous studies suggested NK cells might overexpress CD73, but this has not been consistently demonstrated.
Purpose of the Study:
- To investigate the conditions and extent of CD73 upregulation on NK cells.
- To determine if CD73 expression on NK cells correlates with specific functional characteristics.
- To explore the in vivo relevance of CD73 expression on tumor-infiltrating NK cells.
Main Methods:
- Exposure of NK cells to CD73-expressing cancer cells.
- Analysis of NK cell CD73 surface expression under varying conditions (e.g., hypoxia).
- In vitro functional assays comparing CD73+ and CD73- NK cells.
- Analysis of patient data (glioblastoma) for NK cell marker expression.
Main Results:
- NK cells can upregulate CD73 surface expression in response to CD73+ cancer cells, but this is cancer-specific and environmentally influenced (e.g., hypoxia).
- Upregulation is not universal and often limited in intensity.
- CD73+ NK cells exhibited hyperfunctional characteristics in vitro.
- Glioblastoma patient data revealed variable NK cell CD73 expression, associated with altered expression of CD16, CEACAM1, CXCR3, and TIM-3.
Conclusions:
- NK cells are generally resistant to substantial CD73 upregulation.
- Inducible CD73 expression on NK cells is driven by cancer cell CD73 and microenvironmental factors like hypoxia.
- NK cells expressing CD73 demonstrate distinct functional signatures, suggesting a role in immune modulation within the tumor microenvironment.
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